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Immunostain in short

HSIL showing the characteristic p16 staining. (WC/Nephron)
Similar stains HPV
Use HSIL versus LSIL, HPV associated SCC versus non-HPV associated SCC
Subspeciality gynecologic pathology, head and neck pathology
Normal staining pattern nuclear and cytoplasmic
Positive endometrial tubal metaplasia, cervical SCC, HPV-associated head and neck SCC, serous carcinoma of the endometrium
Endocervical AIS showing the characteristic p16 staining.

p16 is a commonly used immunostain. It can be considered a surrogate marker for HPV infection. p16, like most other "p" stains, is a nuclear stain. The antibody target is a cell cycle protein, cyclin-dependent kinase inhibitor 2A, sometimes denoted p16INK4a.


  • Nuclear stain +/- cytoplasmic staining.


Head and neck squamous cell carcinoma

p16 testing is useful in:

  1. Lymph node metastases with an unknown primary - positivity suggests an oropharyngeal primary.
  2. Oropharyngeal carcinomas.


  • Like elsewhere, i.e. other anatomical sites, p16 is an imperfect surrogate marker for the presence of HPV.[3]
  • Non-oropharyngeal sites (oral cavity, larynx, and hypopharynx) are not well-studied; however, it is known that p16 positivity is much less common in there.[3]




  • Positive staining (in the head and neck pathology context) is defined as (strong block) positive staining in >75% (or >50%) of lesional cells.[7]
    • Staining varies somewhat by the p16 clone used.


  • p16 endometrial tubal metaplasia.[8]

Focal staining



  1. Thway, K.; Flora, R.; Shah, C.; Olmos, D.; Fisher, C. (Mar 2012). "Diagnostic utility of p16, CDK4, and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors.". Am J Surg Pathol 36 (3): 462-9. doi:10.1097/PAS.0b013e3182417330. PMID 22301498.
  2. Koh, SS.; Cassarino, DS. (Jul 2018). "Immunohistochemical Expression of p16 in Melanocytic Lesions: An Updated Review and Meta-analysis.". Arch Pathol Lab Med 142 (7): 815-828. doi:10.5858/arpa.2017-0435-RA. PMID 29939777.
  3. 3.0 3.1 Stephen, JK.; Divine, G.; Chen, KM.; Chitale, D.; Havard, S.; Worsham, MJ. (2013). "Significance of p16 in Site-specific HPV Positive and HPV Negative Head and Neck Squamous Cell Carcinoma.". Cancer Clin Oncol 2 (1): 51-61. doi:10.5539/cco.v2n1p51. PMID 23935769.
  4. Piaton, E.; Casalegno, JS.; Advenier, AS.; Decaussin-Petrucci, M.; Mege-Lechevallier, F.; Ruffion, A.; Mekki, Y. (Oct 2014). "p16(INK4a) overexpression is not linked to oncogenic human papillomaviruses in patients with high-grade urothelial cancer cells.". Cancer Cytopathol 122 (10): 760-9. doi:10.1002/cncy.21462. PMID 25069600.
  5. Chiesa-Vottero, AG.; Malpica, A.; Deavers, MT.; Broaddus, R.; Nuovo, GJ.; Silva, EG. (Jul 2007). "Immunohistochemical overexpression of p16 and p53 in uterine serous carcinoma and ovarian high-grade serous carcinoma.". Int J Gynecol Pathol 26 (3): 328-33. doi:10.1097/01.pgp.0000235065.31301.3e. PMID 17581420.
  6. Švajdler M, Mezencev R, Ondič O, Šašková B, Mukenšnábl P, Michal M (April 2018). "P16 is a useful supplemental diagnostic marker of pulmonary small cell carcinoma in small biopsies and cytology specimens". Ann Diagn Pathol 33: 23–29. doi:10.1016/j.anndiagpath.2017.11.008. PMID 29566943.
  7. Shelton J, Purgina BM, Cipriani NA, Dupont WD, Plummer D, Lewis JS (September 2017). "p16 immunohistochemistry in oropharyngeal squamous cell carcinoma: a comparison of antibody clones using patient outcomes and high-risk human papillomavirus RNA status". Mod Pathol 30 (9): 1194–1203. doi:10.1038/modpathol.2017.31. PMID 28621317.
  8. Horree, N.; Heintz, AP.; Sie-Go, DM.; van Diest, PJ. (2007). "p16 is consistently expressed in endometrial tubal metaplasia.". Cell Oncol 29 (1): 37-45. PMID 17429140.
  9. Stewart, CJ.; Bharat, C. (Feb 2016). "Clinicopathological and immunohistological features of polypoid endometriosis.". Histopathology 68 (3): 398-404. doi:10.1111/his.12755. PMID 26095917.
  10. O'Neill, CJ.; McCluggage, WG. (Jan 2006). "p16 expression in the female genital tract and its value in diagnosis.". Adv Anat Pathol 13 (1): 8-15. doi:10.1097/01.pap.0000201828.92719.f3. PMID 16462152.
  11. Pereira, TC.; Share, SM.; Magalhães, AV.; Silverman, JF. (Jan 2011). "Can we tell the site of origin of metastatic squamous cell carcinoma? An immunohistochemical tissue microarray study of 194 cases.". Appl Immunohistochem Mol Morphol 19 (1): 10-4. doi:10.1097/PAI.0b013e3181ecaf1c. PMID 20823766.
  12. Wang, CW.; Wu, TI.; Yu, CT.; Wu, YC.; Teng, YH.; Chin, SY.; Lai, CH.; Chen, TC. (May 2009). "Usefulness of p16 for differentiating primary pulmonary squamous cell carcinoma from cervical squamous cell carcinoma metastatic to the lung.". Am J Clin Pathol 131 (5): 715-22. doi:10.1309/AJCPTPBC6V5KUITM. PMID 19369633.

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