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Squamous cell carcinoma pathology

Author: Dr Nicholas Turnbull, Dermatopathology Fellow, Warwick, UK; A/Prof Patrick Emanual Dermatopathologist, Auckland, New Zealand. 3 May 2014.

Table of contents

Squamous cell carcinoma (SCC) is common form of keratinocytic skin cancer, usually related to exposure to ultraviolet radiation from sunlight. It often arises within solar/actinic keratosis or within squamous cell carcinoma in situ.

Histology of SCC

Typical SCC has nests of squamous epithelial cells arising from the epidermis and extending into the dermis (figure 1). The malignant cells are often large with abundant eosinophilic cytoplasm and a large, often vesicular, nucleus. Variable keratinisation (keratin pearls etc) is present (figure 2).

Squamous cell carcinoma – typical features

Typically SCC is graded as:

  • Well differentiated (figures 3, 4)
  • Moderately differentiated (figures 5, 6)
  • Poorly differentiated (figures 7, 8)

Grading of SCC depends on how easy it is to recognise the characteristics of squamous epithelium (eg. intracellular bridges, keratinisation), pleomorphism and mitotic activity. There is considerable inter-observer variation in grading SCC.

Squamous cell carcinoma – differentiation

SCC can infiltrate along nerve sheaths, adventitia of blood vessels and lymphatics. Inflammation around these structures may be a clue to tumour in these areas. Tumour cells may evoke a stromal desmoplastic response. Extra-tumoural vascular invasion and neural invasion may be seen (figures 9, small – arrow indicates nerve; 10, large).

Squamous cell carcinoma – neural invasion

Variants of SCC

Spindle cell SCC
Not uncommon. It occurs in sun exposed areas and is associated with a good prognosis. Less commonly spindle cell SCC occurs after ionizing radiation, trauma or sometimes in organ transplant patients. These have worse prognosis (figures 11,12). Spindle cell squamous cell carcinoma pathology
Figure 11
Spindle cell squamous cell carcinoma pathology
Figure 12
Clear cell SCC
Clear cells containing glycogen are seen in a variable proportions of this tumour. A signet ring SCC is a variant demonstrating clear cells with glycogen compressing and displacing the nucleus laterally (figures 13, 14). Clear cell squamous cell carcinoma pathology
Figure 13
Clear cell squamous cell carcinoma pathology
Figure 14
Desmoplastic SCC
High risk of local recurrence and metastases. Nests and strands surrounded by an intense desmoplastic stromal reaction. Cellular pleomorphism and perineural invasion are frequent features. By definition 1/3 of the tumour should be desmoplastic (figures 15, 16). Desmoplastic squamous cell carcinoma pathology
Figure 15
Desmoplastic squamous cell carcinoma pathology
Figure 16
Verrucous carcinoma
High recurrence rate but metastases are rare (except anogenital lesions, which may be related to HPV). Exo-endophytic lesions with bulbous profile and pushing margins. Pleomorphism and mitotic activity is usually minimal and peripheral(figures 17, 18; 18 (B) shows HPV effect). Verrucous carcinoma pathology
Figure 17
Desmoplastic squamous cell carcinoma pathology
Figure 18
Follicular SCC
Frequently found on the head and neck. Develop in the upper part of the hair follicles (figures 19, 20, 21). Follicular squamous cell carcinoma pathology
Figure 19
Follicular squamous cell carcinoma pathology
Figure 20
Follicular squamous cell carcinoma pathology
Figure 21
Keratoacanthoma-like SCC
Some consider keratoacanthoma (KA) within the spectrum of well differentiated SCC. This subtype is somewhat controversial (figures 22, 23, 24). Keratoacanthoma pathology
Figure 22
Keratoacanthoma pathology
Figure 23
Keratoacanthoma pathology
Figure 24
Acantholytic SCC
Uncommon variant (2-4%). Central acantholysis leading to an impression of gland formation (figures 25, 26). Acantholytic squamous cell carcinoma pathology
Figure 25
Acantholytic squamous cell carcinoma pathology
Figure 26
Pseudovascular SCC
Tends to affect men again in sun exposed sites. Recurrence and metastatic rate is high as is mortality. Rare as a primary skin SCC (figure 27). Pseudovascular squamous cell carcinoma pathology
Figure 27
Adenosquamous carcinoma/mucoepidermoid carcinoma of the skin
Cutaneous SCC with glandular differentiation is rare. The head and neck are almost exclusively affected. Glandular differentiation may be sparse (figures 28, 29). Adenosquamous carcinoma pathology
Figure 28
Adenosquamous carcinoma pathology
Figure 29
Metaplastic SCC (carcinosarcoma, carcinoma with heterologous differentiation)
Exceedingly rare. This is a biphasic tumour with malignant epithelial (SCC, BCC or adnexal malignancy) and mesenchymal components (figures 30, 31). Carcinosarcoma pathology
Figure 30
Carcinosarcoma pathology
Figure 31
Inflammatory SCC
Dense lymphocytic stromal infiltrate surrounding poorly differentiated squamous nests. This SCC has high metastatic potential (figures 32, 33). Inflammatory squamous cell carcinoma pathology
Figure 32
Inflammatory squamous cell carcinoma pathology
Figure 33
Basaloid SCC
Found in the oropharynx and anogenital region. High association with HPV infection in anogenital lesions. Small basaloid cells with a high mitotic rate (figures 34, 35) Basaloid squamous cell carcinoma pathology
Figure 34
Basaloid squamous cell carcinoma pathology
Figure 35
Infiltrative SCC
Small nests and strands or single cells infiltrating a dermis which is fibrous and/or mucinous (figure 36). Infiltrative squamous cell carcinoma pathology
Figure 36
Pigmented SCC
Melanin is found in epithelial tumour cells as well as in macrophages and dendritic melanocytes. This variant must be distinguished from the squamomelanocytic tumour, in which both a squamous cell carcinoma and melanoma components may occur.      
Pseudohyperplastic SCC
Non-verruciform lesion that occurs on the penis. Associated with lichen sclerosus. Well-differentiated keratinizing nests of squamous cells with minimal atypia surrounded by a reactive fibrous stroma.      
Squamous cell carcinoma variants pathology

Special stains in SCC

Immunoperoxidase staining may be helpful in poorly differentiated and spindle cell-type SCC. EMA, MNF116, cytokeratin5/6 and p63 are expressed in SCC.

Differential diagnosis of SCC

SCC is usually not difficult to recognize pathologically. Deciding if the lesion is invasive or in situ can be more difficult, requiring levels through the specimen to be examined. Benign epithelial changes seen in the context of ulceration, stasis changes or infection can mimic SCC including:

  • Reactive atypia
  • Pseudoepitheliomatous hyperplasia
  • Eccrine squamous syringometaplasia
  • Viral changes

Other tumours may resemble SCC eg keratoacanthoma.

The differential diagnosis of SCC variants can be extensive.

  • Clear cell SCC can resemble sebaceous carcinoma or balloon cell melanoma, etc.
  • Acantholytic SCC may resemble angiosarcoma or adenocarcinoma. Clues these variants are SCC are often found in other parts of the lesion.
  • Spindle cell SCC often requires immunohistochemistry for distinction from differential diagnoses including: leiomyosarcoma, angiosarcoma, melanoma, undifferentiated sarcoma, atypical fibroxanthoma, nodular fasciitis, Kaposi sarcoma, dermatofibrosarcoma protruberans.



  • Weedon D. Skin pathology, Third Edition. Elseiver Ltd. 2010; Squamous cell carcinoma p.691–700
  • Calonje E, Brenn T, Lazar A, McKee PH. McKee’s Pathology of the Skin with Clinical Correlations (4th edition), pp 1115–1140. China: Elsevier Saunders, 2011.

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