Before the interpretation of a pan-cytokeratin stain, it is always to consider that there is no pan-cytokeratin that reacts absolutely with all cytokeratins; nevertheless, cytokeratin cocktails are very effective in screening for epithelial differentiation or epithelial neoplasms [6]. The following cytokeratin cocktails and clones are the most commonly used markers in routine immunohistochemistry:

Different cytokeratins are also expressed in various non-epithelial tissue types and neoplasms or in tumors with features of epithelial differentiation. The following list represents the most popular examples:

The aberrant expression of cytokeratin in mesenchymal tumors is usually patchy and may show dot-like expression pattern. The diagnosis of carcinoma based only on a positive pan-cytokeratin reaction is one of the sources of serious mistakes in tumor diagnosis. For appropriate diagnosis, it is always advisable to determine the cytokeratin profile of the tumor and then to search for other tissue-specific markers. Ectopic benign epithelial structures in lymph nodes such as heterotopic ducts and glands in cervical, thoracic, and abdominal lymph nodes in addition to Müllerian epithelial inclusions and endometriosis in pelvic lymph nodes must be kept in mind in screening lymph nodes for metastatic carcinoma or disseminated tumor cells (Fig. 2.1).

Cytokeratin 5 is a type II cytokeratin and a main component of the cytoskeleton of basal cells of stratified epithelium. Cytokeratins 5, 6, and 14 are related cytokeratins expressed in stratified squamous epithelium, myoepithelium, and mesothelium. This expression spectrum makes these cytokeratins valuable markers for the diagnosis of squamous cell carcinoma. They also clearly label normal myoepithelial cells, myoepithelial cell components in some tumors such as salivary gland tumors and myoepithelial tumors. Highlighting the myoepithelial cells using this group of cytokeratins is essential for the interpretation of prostatic biopsies, as basal cells are absent in neoplastic prostatic glands. An identical approach is also important to distinguish between simple hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ (DCIS) in breast biopsies highlighting the myoepithelial and luminal cells with the cytokeratins 5/6/14 and 8/18, respectively. Cytokeratins 5/6/14 are highly expressed in mesothelial cells and are not suitable for discriminating between squamous cell carcinoma and mesothelioma in pleural or peritoneal biopsies or cytology (Fig. 2.2). This group of cytokeratins is usually absent in gastrointestinal adenocarcinomas, germ cell tumors, prostatic carcinoma, thyroid tumors, and hepatocellular and renal cell carcinomas.

Recently, CK5/14 is frequently replaced by p63 and p40 that highlights the nuclei of myoepithelial and basal cells of the glands as well as the basal and intermediate cells of squamous epithelium and urothelium [1]. Both markers are discussed below.

Cytokeratin 6 is a type I cytokeratin with the same tissue distribution as cytokeratin 5 and is usually used in routine immunohistochemistry as cocktail with cytokeratin 5.

Cytokeratin 7 is a type II cytokeratin expressed in the majority of ductal and glandular epithelium in addition to transitional epithelium of the urinary tract. Cytokeratin 7 is one of the main markers for the diagnosis of adenocarcinoma of different origin; hence, it cannot be used alone to differentiate between primary and metastatic adenocarcinoma. An important diagnostic criterion is the co-expression of cytokeratin 7 and cytokeratin 20 (see diagnostic algorithms 1.6, 1.7, and 1.8) [2]. Cytokeratin 7 is strongly expressed by mesothelial cells and not suitable for discriminating between adenocarcinoma and mesothelioma.

In the differential diagnosis between adenocarcinoma and squamous cell carcinoma, it is important to keep in mind that a minor component of cytokeratin 7-positive cells can be found in squamous cell carcinoma of different locations including carcinoma of the head and neck, lung, esophagus, and uterine cervix, mainly in poorly differentiated carcinoma. Cytokeratin 7 can also be expressed in non-epithelial tumors such as the epithelioid component of synovial sarcoma. Cytokeratin 7 is usually absent in seminoma and yolk sac tumors, epidermal squamous cell carcinoma, prostatic carcinoma, and pituitary tumors.

Cytokeratin 8 is a type II cytokeratin usually building heterodimer with cytokeratin 18. Both cytokeratins 8 and 18 are intermediate filament proteins expressed in the early embryonal stages and persist in adult simple epithelium. Cytokeratin 8 is usually positive in non-squamous carcinomas and accordingly cannot be used to discriminate between adenocarcinoma types. Cytokeratin 8b stains also few mesenchymal tumors such smooth muscle tumors and malignant rhabdoid tumor.

Cytokeratin 8 reacts with several non-epithelial tissues and tumors such as smooth muscle cells and leiomyosarcoma.

Cytokeratin 10 is type I cytokeratin and intermediate filament usually associated with cytokeratin 1. Cytokeratin 10 is expressed in keratinizing and nonkeratinizing squamous epithelium. In routine immunohistochemistry, cytokeratin 10 is used in a cocktail with cytokeratins 13 and 14 as marker for squamous cell carcinoma.