• Cytoskeletal proteins that belong to the family of intermediate filaments (IFs) (Cell Biol Int 2018;42:132)
• Most fundamental markers of epithelial differentiation (Semin Cancer Biol 2022;86:816)

• Cytoskeleton of eukaryotic cells is responsible for mechanical integrity of cells and plays a role in cell division, motility and cell to cell contact (Cell Biol Int 2018;42:132)
• Cytoskeleton consists of 3 different types of filamentous structures (Nature 2010;463:485)
  • Microfilaments
  • Microtubules
  • Intermediate filaments (IFs)
• Intermediate filament family includes (Curr Opin Cell Biol 2024;87:102325)
  • Cytokeratins (CKs) → marker for epithelial differentiation
  • Vimentin → marker for mesenchymal differentiation
  • Glial fibrillary acidic proteins (GFAP) → marker for glial differentiation
  • Desmin → marker for muscular differentiation
• Over 25 subtypes of CKs are defined based on molecular weight (40 to 68 kDa) and isoelectric pH (5 to 8) (Acta Histochem Suppl 1991;41:117)
• Moll catalog number ranges from 1 (highest molecular weight) to 23 (lowest molecular weight) (Cell 1982;31:11)
• New nomenclature has been proposed (J Cell Biol 2006;174:169)
• CKs are grouped into 2 main categories for diagnostic purposes
  • Acidic CKs (type A / class I)
  • Basic CKs (type B / class II)
• These 2 groups are further designated based on their migration pattern in a 2 dimensional (2D) gel electrophoresis, which separates them based on size (Semin Cancer Biol 2022;86:816)
  • For diagnostic purposes, CKs are divided into low molecular weight cytokeratins (LMWCK) and high molecular weight cytokeratins (HMWCK)
• 28 genes coding for acidic CKs clustered at long arm of chromosome 17 (17q21.2) and 26 genes coding for basic CKs at long arm of chromosome 12 (12q13.13) (Hum Genomics 2022;16:1)
• CKs assemble into obligate noncovalent heterodimers containing 1 cytokeratin protein of type A / class I and 1 cytokeratin protein of type B / class II (e.g., CK8/18, CK5/14, etc.) (PLoS One 2015;10:e0132706)
• All CKs dimers have the same tridomain structure: a head, a central rod and a tail domain (Semin Cell Dev Biol 2022;128:80)
• During the transformation of normal cells into malignant cells, the cytokeratin patterns are usually maintained: this property allows cytokeratins to be applied as reliable markers for epithelial differentiation (Cold Spring Harb Perspect Biol 2018;10:a018275)

Contributed by Umberto Maccio, M.D., M.Sc., M.B.A.


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Contributed by Umberto Maccio, M.D., M.Sc., M.B.A.

• Carcinomas (Cancers (Basel) 2018;10:108)
• Positive in tumors with epithelial differentiation, which can be identified with electron microscopy, even in tumors that are not classified strictly as carcinomas) (Histopathology 2014;64:101)
  • Synovial sarcoma
  • Epithelioid sarcoma
  • Epithelioid angiosarcoma
  • Rhabdomyosarcoma (more common in alveolar type)
  • Leiomyosarcoma
  • Mesothelioma
  • Nonseminoma germ cell tumors (embryonal carcinoma, yolk sac tumor)
  • Chordoma
  • Thymoma
• Some gliomas and reactive astrocytes (due to crossreactivity between AE3 and GFAP, as in schwannoma) (Virchows Arch 1997;431:139, Mod Pathol 2006;19:115)

• The Human Protein Atlas: Cytokeratins [Accessed 29 October 2024], Proteopedia: Keratins [Accessed 29 October 2024]

An endometrial biopsy showed atypical isolated cells in endometrial stroma. Immunohistochemistry for AE1 / AE3 is shown in the picture above. Which of the following statements is correct?

1. AE1 / AE3 positivity in the atypical cells is diagnostic for carcinoma
2. AE1 / AE3 positivity in the atypical cells is suggestive of carcinoma, although other markers and correlation with the clinical context are required for a definitive diagnosis
3. AE1 / AE3 positivity rules out a hematological neoplasia
4. AE1 / AE3 positivity rules out a sarcoma

B. AE1 / AE3 positivity in the atypical cells is suggestive of carcinoma, although other markers and correlation with the clinical context are required for a definitive diagnosis. AE1 / AE3 positivity, especially when combined with morphological features indicative of carcinoma, is suggestive for this diagnosis but this must be interpreted within the appropriate clinical context (e.g., the image shown above is a metastatic lobular breast carcinoma to the endometrium; therefore, the AE1 / AE3 positive cells could support a diagnosis consistent with metastasis). Answer A is incorrect because AE1 / AE3 positivity can be observed in many other tumors (e.g., some sarcomas or melanomas) so the diagnosis of carcinoma can only be made if the morphology and the clinical context are appropriate and should be done with great caution in cases of cancer of unknown primary. Answer C is incorrect because AE1 / AE3 can be aberrantly expressed in some lymphomas. Answer D is incorrect because AE1 / AE3 can be expressed in various sarcomas.

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Reference: Cytokeratins (CK) - general

Which of the following best describes the structure of cytokeratins?

1. Cytokeratins are composed of microfilaments and are responsible for cell motility
2. Cytokeratins are intermediate filaments and each cytokeratin dimer has a tridomain structure consisting of a head, a central rod and a tail domain
3. Cytokeratins belong to the family of microtubules and provide tensile strength to cells
4. Cytokeratins are essential components of the extracellular matrix, playing a role in cell adhesion

B. Cytokeratins are intermediate filaments and each cytokeratin dimer has a tridomain structure consisting of a head, a central rod and a tail domain. Cytokeratins are classified as intermediate filaments, not microfilaments or microtubules. They have a characteristic dimer structure which is essential for their function in providing structural support and maintaining cellular integrity. Unlike microflaments, which are involved in cell motility, cytokeratins primarily contribute to the mechanical stability of cells, especially in epithelial tissues. Answer A is incorrect because microfilaments, not cytokeratins, are primarily responsible for cell motility. Answer C is incorrect because cytokeratins are not microtubules but intermediate filaments. Answer D is incorrect because cytokeratins are cytoskeletal components, not extracellular matrix proteins.

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Reference: Cytokeratins (CK) - general

Cytokeratins (CKs) are classified based on their molecular weight and isoelectric pH. Which of the following statements accurately describes the classification of CKs?

1. CKs are divided into 2 groups: basic CKs (type B / class II) and acidic CKs (type A / class I) and they always form homodimers
2. CKs are divided into 2 groups: basic CKs (type B / class II) and acidic CKs (type A / class I) and they form obligate heterodimers
3. CKs are divided based on their expression in carcinomas versus sarcomas
4. CKs are classified solely based on their tissue of origin

B. CKs are divided into 2 groups: basic CKs (type B / class II) and acidic CKs (type A / class I) and they form obligate heterodimers. CKs are categorized into basic and acidic groups according to their molecular weight and isoelectric points. Rather than forming homodimers, CKs form obligate heterodimers, with each pair consisting of one acidic CK and one basic CK. Answer A is incorrect because CKs do not form homodimers. Answer C is incorrect because CK classification is not based on their presence in carcinomas or sarcomas but on their molecular characteristics. Answer D is incorrect because CK classification involves molecular weight and pH, not just tissue of origin.

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Reference: Cytokeratins (CK) - general