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Stains & CD markers
Cytokeratin AE1 / AE3

Mieke R. Van Bockstal, M.D., Ph.D.

Last author update: 16 June 2022
Last staff update: 16 June 2022

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PubMed Search: Cytokeratin AE1 / AE3

Mieke R. Van Bockstal, M.D., Ph.D.
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Table of Contents
Definition / general | Essential features | Terminology | Pathophysiology | Interpretation | Uses by pathologists | Prognostic factors | Microscopic (histologic) images | Cytology images | Positive staining - normal | Positive staining - disease | Negative staining | Sample pathology report | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3
Cite this page: Van Bockstal MR. Cytokeratin AE1 / AE3. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsae1ae3.html. Accessed June 10th, 2023.
Definition / general
  • Mixture of 2 different clones of anticytokeratin (CK) monoclonal antibodies (AE1 and AE3), which functions as a broad spectrum cytokeratin marker (Ann Surg Oncol 2011;18:S261)
  • AE1 detects the high molecular weight cytokeratins 10, 14, 15 and 16 and the low molecular weight cytokeratin 19
  • AE3 detects the high molecular weight cytokeratins 1, 2, 3, 4, 5 and 6 and the low molecular weight cytokeratins 7 and 8
  • Not reactive to cytokeratins 17 and 18
Essential features
  • Mixture of 2 different clones of anticytokeratin monoclonal antibodies (AE1 and AE3), which functions as a broad spectrum cytokeratin marker for cytokeratins 1 - 8, 10, 14 - 16 and 19
  • Immunoreactivity is observed in epithelia and most carcinomas (i.e., tumors of epithelial origin), with cytoplasmic and membranous positivity
  • Normal liver is recommended as an on slide positive external control
  • CK AE1 / AE3 immunohistochemistry is used for assessment of occult lymph node metastases, residual disease after neoadjuvant therapy, invasion depth and tumor budding in multiple carcinomas
  • CK AE1 / AE3 is rarely used as a standalone immunohistochemical analysis but rather as part of a panel when used to confirm or rule out epithelial nature of tumors
Terminology
  • Pankeratin, broad spectrum keratin or keratin: not preferred as this can also refer to cytokeratin MNF116 and (to a lesser extent) CAM5.2
Pathophysiology
  • Cytokeratins are proteins of the cytoskeletal intermediate filaments, which allow cells to cope with mechanical stress
  • Type I cytokeratins are acidic and type II cytokeratins are basic, either with high or low molecular weight; acidic and basic cytokeratins often form heterodimeric pairs (Ann N Y Acad Sci 1985;455:282)
  • Their expression varies throughout the tissue type and is mainly organ specific, which allows their use to identify the primary origin of a metastatic tumor (Ann N Y Acad Sci 1985;455:282, Arch Pathol Lab Med 2017;141:1014)
Interpretation
  • Normal pattern in epithelium: cytoplasmic staining reaction with accentuation of the cellular membrane
  • Dot-like pattern in certain tumors, such as neuroendocrine neoplasms
Uses by pathologists
Prognostic factors
  • Micrometastases and isolated tumor cells are generally associated with poorer prognosis in many cancer types:
    • Occult tumor cells are associated with poor recurrence free survival and increased risk of cancer related death in gastric cancer patients staged as pN0 (Ann Surg Oncol 2020;27:4204)
    • Micrometastasis is associated with worse recurrence free survival and overall survival in stage I lung adenocarcinoma (Am J Surg Pathol 2017;41:1212)
    • Lymph node micrometastasis is more frequently observed in stage I lung adenocarcinoma with a micropapillary component (Am J Surg Pathol 2017;41:1212)
    • Presence of micrometastases and isolated tumor cells in (early stage) breast cancer is associated with poorer disease free and overall survival; however, NSABP-32 findings support that local radiation and systemic therapy, particularly endocrine therapy, may attenuate the unfavorable effect (J Natl Cancer Inst 2010;102:410, Br J Cancer 2018;118:1529, N Engl J Med 2011;364:412)
    • CK AE1 / AE3 immunohistochemistry is not recommended for routine evaluation of pelvic lymph nodes in prostate cancer patients as it does not reveal additional information to a standard hematoxylin and eosin section (Virchows Arch 2014;464:45)
  • Although tumor budding is assessed in one hotspot at the invasive front (in a field measuring 0.785 mm2) of a single hematoxylin / eosin stained slide, CK AE1 / AE3 immunohistochemistry may help to identify hotspots (Virchows Arch 2021;479:459, Mod Pathol 2017;30:1299)
  • Tumor budding is associated with poor prognosis in several cancer types:
    • High budding in colorectal carcinoma is associated with higher tumor grade, higher TNM stage, vascular invasion and reduced survival (Mod Pathol 2013;26:295)
    • Tumor budding in colorectal carcinoma is classified as follows (Mod Pathol 2017;30:1299):
      • Bd1 (low budding) : 0 - 4 buds per 0.785 mm2
      • Bd2 (intermediate budding) : 5 - 9 buds per 0.785 mm2
      • Bd3 (high) : ≥ 10 buds per 0.785 mm2
    • Tumor budding in tongue squamous cell carcinoma and colorectal carcinoma is defined as a single cancer cell or small cluster of < 5 cancer cells at the tumor's invasive front (Hum Pathol 2018;76:1, Mod Pathol 2017;30:1299)
    • Tumor budding score ≥ 4 is a significant predictor of occult metastasis in cT2N0 tongue squamous cell carcinoma (Hum Pathol 2018;76:1)
    • High tumor budding is associated with worse overall survival in resected esophageal adenocarcinoma (Virchows Arch 2021;478:393)
Microscopic (histologic) images

Contributed by Mieke R. Van Bockstal, M.D., Ph.D., Christine Galant, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.
Serous carcinoma   Serous carcinoma

Serous carcinoma

Mammary spindle cell carcinoma   Mammary spindle cell carcinoma

Mammary spindle cell carcinoma

Mammary desmoid fibromatosis   Mammary desmoid fibromatosis

Mammary desmoid fibromatosis


Residual breast carcinoma   Residual breast carcinoma

Residual breast carcinoma

Ileal neuroendocrine tumor   Ileal neuroendocrine tumor

Ileal neuroendocrine tumor

Chordoma   Chordoma

Chordoma


Juvenile granulosa cell tumor   Juvenile granulosa cell tumor

Juvenile granulosa cell tumor

Sertoli-Leydig cell tumor   Sertoli-Leydig cell tumor

Sertoli-Leydig cell tumor

Uterine tumor resembling ovarian sex cord tumor (UTROSCT)   Uterine tumor resembling ovarian sex cord tumor (UTROSCT)

Uterine tumor resembling ovarian sex cord tumor (UTROSCT)


Normal liver   Normal liver

Normal liver

Normal lymph node

Normal lymph node

Gastric MALT lymphoma   Gastric MALT lymphoma

Gastric MALT lymphoma

Papillary thyroid cancer

Papillary thyroid cancer

Cytology images

Images hosted on other servers:
CK AE1 / AE3 highlights reactive mesothelial cells

CK AE1 / AE3 highlights reactive mesothelial cells

Positive staining - normal
Positive staining - disease
Negative staining
Sample pathology report
  • Immunohistochemical analysis for cytokeratin AE1 / AE3, performed on an automated slide stainer (brand name):
    • The tissue sample shows no / focal / diffuse* dot-like / cytoplasmic / membrane* staining with weak / moderate / strong* intensity.
    • External on slide tissue control (liver - in accordance with the NordiQC recommendations): positive
  • * Select the appropriate option

  • Biopsy, left breast (external superior quadrant):
    • Desmoid fibromatosis of the breast, with presence of an APC gene mutation (see comment)
    • Number of biopsies: 2
    • Maximum length of the biopsy: 14 mm
    • Lesion type / histological description: Both biopsies show a spindle cell proliferation with fascicular architecture. In one of these biopsies, diffuse infiltration of the fatty stroma is observed. The spindle cells are bland, elongated and slender, with a pale slightly eosinophilic cytoplasm. They are surrounded by a densely collagenous stroma. There is no overt cytonuclear atypia, no clear nucleoli and no nuclear hyperchromasia. There are < 1 mitosis per 10 high power fields.
    • Presence of calcifications: no
    • Immunohistochemistry and discussion: Immunohistochemical stains for p63, cytokeratin AE1 / AE3, cytokeratin 8/18 and cytokeratin 34betaE12 are negative, which excludes a low grade fibromatosis-like metaplastic breast carcinoma. Immunohistochemical stains for SOX10 and S100 are negative, which excludes a neurofibroma. There is no immunoreactivity for desmin, which excludes a leiomyoma. Immunohistochemistry for CD34 is negative, which excludes a myofibroblastoma and PASH with fascicular architecture. The spindle cells show cytoplasmic immunoreactivity for SMA and beta catenin. There is no nuclear expression of beta catenin.
    • Molecular analysis and discussion: FISH analysis did not show USP6 rearrangement, which excludes a nodular fasciitis. Next generation sequencing of the tumor sample did not show any mutations in the CTNNB1 gene but revealed a c.4626_4645del; p.(Lys1543Argfs*9) mutation in the APC gene, with a variant allele frequency of 52%.
    • Comment: APC gene mutations are commonly observed in breast desmoid fibromatosis and might either be somatic or germline (Am J Surg Pathol 2020;44:1266).
    • Recommendation: These findings are to be correlated with the clinical history and family history of the patient, as a germline APC mutation (Gardner / familial adenomatous polyposis syndrome) should be excluded.
Board review style question #1
Which of the following tissues is the best choice as a positive on slide control for cytokeratin AE1 / AE3 immunohistochemistry?

  1. Adrenal gland
  2. Appendix
  3. Gastric mucosa
  4. Liver
  5. Placenta
Board review style answer #1
D. Liver. The liver shows strong, distinct cytoplasmic immunoreactivity of all bile ductal epithelial cells, as well as at least moderate cytoplasmic staining of the majority of hepatocytes. Hepatocytes show membrane accentuation. A low expressor (such as hepatocytes) is required to enable the detection of a slightly failing immunohistochemical staining reaction (resulting in insufficient intensity in low expressors), as strong expressors (such as most epithelia) will still present with an intense cytoplasmic staining.

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Reference: Cytokeratin AE1 / AE3
Board review style question #2
Which of the following tumors is predominantly positive for cytokeratin AE1 / AE3?

  1. Adrenocortical carcinoma
  2. Aggressive angiomyxoma
  3. Benign meningioma
  4. Paraganglioma
  5. STK11 adnexal tumor
Board review style answer #2
E. STK11 adnexal tumor. 93% of STK11 adnexal tumors present at least some immunoreactivity for CK AE1 / AE3, whereas 72% of aggressive angiomyxomas are negative for CK AE1 / AE3. Nearly all benign meningiomas, 84% of adrenocortical carcinomas and 98% of paragangliomas do not present any immunoreactivity for CK AE1 / AE3.

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Reference: Cytokeratin AE1 / AE3
Board review style question #3


This tissue was stained for cytokeratin AE1 / AE3. Which is the correct statement?

  1. The protocol of this immunohistochemical stain should be revised as lymphoid tissue should not show any immunoreactivity for cytokeratin AE1 / AE3
  2. This axillary lymph node contains isolated tumor cells from an invasive lobular carcinoma of the breast
  3. This axillary lymph node shows weak to moderate cytoplasmic staining in interstitial reticulum cells with dendritic / reticular pattern
  4. This immunohistochemical staining pattern is compatible with a nodal histiocytic sarcoma
Board review style answer #3
C. This axillary lymph node shows weak to moderate cytoplasmic staining in interstitial reticulum cells with dendritic / reticular pattern. The tissue shown in the photograph is a normal lymph node. A weak to moderate cytoplasmic staining reaction in the interstitial reticulum cells of a lymph node is normal and therefore the protocol of this stain should not be revised. Normal liver is a better external control tissue than a lymph node, as it contains both low and high expressors of CK AE1 / AE3.

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Reference: Cytokeratin AE1 / AE3
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