What are the brief histopathological features of squamous cell carcinoma and how is it graded?

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Histopathological Features and Grading of Squamous Cell Carcinoma

Squamous cell carcinoma is characterized histologically by recognizably squamous cells with keratinization and intercellular bridges, but importantly, histopathologic grading systems (including the Broders system) fail to correlate reliably with prognosis and are therefore optional for reporting. 1

Core Histopathological Features

Defining Characteristics

Squamous cell carcinomas demonstrate cells with squamous differentiation that vary in growth pattern and cytological morphology. The hallmark features include 2, 3:

  • Keratinization: Individual cell keratinization, keratin pearls, or large central keratin masses
  • Intercellular bridges: Connections between tumor cells
  • Variable cellular atypia: Nuclear pleomorphism and hyperchromasia
  • Mitotic activity: Frequency varies with differentiation level

Histologic Subtypes

The WHO-adopted classification recognizes several types 1:

Keratinizing type: Requires the presence of keratin pearls; mitoses are typically not frequent 3

Nonkeratinizing type:

  • Does not form keratin pearls by definition
  • May show individual cell keratinization
  • Includes large cell and small cell variants (optional designation)
  • Tumor cells may have clear cytoplasm or eosinophilic cytoplasm with distinct cell borders
  • Clear-cell change should not be misinterpreted as clear-cell carcinoma 3

Specialized variants 1:

  • Verrucous carcinoma
  • Warty (condylomatous) carcinoma
  • Papillary squamous cell (transitional) carcinoma
  • Lymphoepithelioma-like carcinoma

Grading Systems: A Critical Limitation

The most important clinical point is that histopathologic grading is optional because multiple studies demonstrate that grading systems, including the commonly used Broders modification, fail to correlate reliably with prognosis. 1

This represents a significant departure from other malignancies and reflects the reality that clinical and anatomic factors (tumor size, depth, location, perineural invasion) are far more predictive of outcomes than cellular differentiation grade.

Traditional Grading (When Reported)

Despite limited prognostic value, when grading is performed, it typically follows differentiation patterns:

Well-differentiated:

  • Abundant keratinization
  • Keratin pearl formation
  • Minimal nuclear pleomorphism
  • Infrequent mitoses

Moderately differentiated:

  • Intermediate keratinization
  • Moderate nuclear atypia
  • More frequent mitoses

Poorly differentiated:

  • Minimal keratinization
  • Marked nuclear pleomorphism
  • Abundant mitoses with abnormal forms
  • May show necrosis

Prognostically Important Histologic Parameters

Rather than grade, pathology reports should focus on features that actually predict outcomes 4, 5:

Critical Features to Report

Depth of invasion 4, 5:

  • Measured in millimeters from granular layer (excluding surface keratin)
  • Tumors >4 mm depth have 45.7% metastatic rate
  • Tumors <4 mm depth have 6.7% metastatic rate
  • Clark level (particularly level IV or V)

Perineural invasion 5:

  • Presence or absence must be documented
  • Diameter of largest affected nerve (especially ≥0.1 mm) when present

Lymphovascular invasion 5:

  • Significantly impacts prognosis
  • Should be specifically noted

Aggressive histologic subtypes 5:

  • Acantholytic
  • Adenosquamous
  • Carcinosarcomatous
  • Desmoplastic (particularly high risk) 6

Growth pattern 6:

  • Endophytic tumors are more malignant than exophytic
  • Ulceration increases recurrence and metastatic risk

Margin status 5:

  • Most important treatment consideration
  • Lateral and deep margins must be assessed

Common Pitfalls

Do not confuse small cell squamous carcinoma with small cell neuroendocrine carcinoma: Small cell poorly differentiated carcinomas with neuroendocrine features (by immunohistochemistry or ultrastructure) are classified as neuroendocrine carcinomas, not squamous cell carcinoma 1

Do not rely on grade alone for risk stratification: Clinical factors (size >2 cm, anatomic site, immunosuppression, depth >4 mm) are more predictive than histologic grade 4

Microinvasive criteria vary by organization 1:

  • SGO: ≤3 mm invasion without angiolymphatic invasion
  • FIGO: ≤5 mm depth and ≤7 mm horizontal dimension

References

5
Guideline

guidelines of care for the management of cutaneous squamous cell carcinoma.

Journal of the American Academy of Dermatology, 2018

6
Research

Squamous cell carcinoma of the skin--histopathological features and their significance for the clinical outcome.

Journal of the European Academy of Dermatology and Venereology : JEADV, 1998

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