• Tumor suppressor protein encoded by CDKN2A gene (9p21.3)
• Prevents progression into S phase of cell cycle
  • Inhibits cyclin D dependent protein kinases (CDK4 and CDK6) therefore maintaining Rb in its hypophosphorylated state which prevents its dissociation from E2F transcription factor
• Protein expression often increased in aging cells, which eventually drives cell death and apoptosis (Exp Cell Res 1997;237:7)
• Protein function is silenced or lost in many non HPV related tumors by epigenetic or genetic abnormalities, including promoter CpG methylation or less commonly by mutations
  • Examples include breast carcinoma, colon carcinoma, pancreatic carcinoma, head and neck carcinoma related to smoking and melanoma

• Expression can be detected by immunohistochemistry
  • Negative IHC in tumors with loss of p16 protein function / expression
  • Immunohistochemical positivity commonly considered a surrogate marker for oncogenic HPV infection
    • Inactivation of Rb by the viral E7 oncoprotein following viral integration into host genome leads to overexpression of p16 (Arch Pathol Lab Med 2007;131:1343)
  • Positivity also seen in lesions with inactivation of Rb due to HPV independent mechanisms, such as Rb gene alterations or other mechanisms of Rb pathway dysregulation
    • Includes liposarcoma, gastric adenocarcinoma, Hodgkin and non-Hodgkin lymphoma, pulmonary adenocarcinoma, neuroendocrine carcinoma and a subset of uterine carcinoma
• Most commonly studied and used in the evaluation of anogenital lesions (cervical, vulvar, vaginal, anal, penile)
• Also useful in the evaluation of head and neck carcinoma (specifically oropharyngeal carcinoma - tonsils, base of tongue)
• Increasingly used in the evaluation of different gynecologic tract tumors: p16 overexpression is more frequently seen in high grade endometrial and ovarian carcinoma (serous, clear cell, high grade endometrioid) compared to low grade tumors (Adv Anat Pathol 2009;16:267, Int J Gynecol Pathol 2009;28:179)
• More frequently overexpressed in uterine leiomyosarcoma, in comparison to STUMP, leiomyoma and inflammatory myofibroblastic tumor (Int J Clin Exp Pathol 2015;8:2795, Histopathol 2017;70:1138)
• Limited value in the workup of unknown primaries, as the protein is expressed in a variety of tumors from a variety of sites (Hum Pathol 2012;43:327)

• p16 protein, also known as multiple tumor suppressor 1 (MTS1) or cyclin dependent kinase inhibitor 2A; also known as p16 INK4a

• Positive staining is defined as "block" staining: strong nuclear and cytoplasmic expression in a continuous segment of cells (at least 10 - 20 cells); in squamous epithelium, block positivity needs to involve basal and parabasal layers
• Positive staining (overexpression) correlates with oncogenic HPV infection and HPV independent mechanisms as outlined above
  • In addition, complete absence of staining is also abnormal, since it has been correlated with CDKN2A gene silencing mutations (Histopathol 2017;70:1138)
• Cytoplasmic only staining, diffuse blush / weak intensity staining and other focal / patchy patterns should be considered negative (Arch Pathol Lab Med 2012;136:1266)

Contributed by Jijgee Munkhdelger, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.


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According to the LAST Project working group recommendations, p16 immunohistochemistry is recommended in all of the following clinical scenarios involving anogenital squamous lesions, EXCEPT:

1. Routinely in the evaluation of biopsies with interpretations of negative, CIN I or CIN III
2. When a biopsy interpretation is < CIN I in the setting of a prior HSIL Pap smear
3. When a diagnosis of CIN II is entertained by H&E morphologic interpretation
4. When the H&E morphologic differential is between a precancerous (CIN II or CIN III) lesion and a mimic of a precancerous lesion (ex. immature squamous metaplasia, atrophy)
5. When there is professional disagreement in histologic interpretation (when the differential diagnosis includes CIN I or III)

A. p16 immunohistochemistry is not recommended as a routine adjunct assessment when the biopsy interpretation is negative, CIN I or CIN III. Strong and diffuse block staining for p16 supports a categorization of precancerous disease. Any identified p16 positive area must meet H&E morphologic criteria for a high grade lesion to reinterpreted as such. (Arch Pathol Lab Med 2012;136:1266)

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Reference: p16