Premalignant / preinvasive lesions - H&E

SMILE (stratified mucin producing intraepithelial lesions)

Topic Completed: 1 August 2017

Minor changes: 12 October 2021

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PubMed Search: Stratified mucin producing intraepithelial lesions cervix

Anjelica Hodgson, M.D.
Carlos Parra-Herran, M.D.
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Cite this page: Hodgson A, Parra-Herran C. SMILE (stratified mucin producing intraepithelial lesions). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cervixSMILE.html. Accessed January 21st, 2022.
Definition / general
  • Rare HPV associated premalignant cervical intraepithelial lesion arising in reserve cells of transformation zone, originally described in 2000 (Am J Surg Pathol 2000;24:1414)
    • These cells can transdifferentiate throughout the carcinogenic process
  • SMILE shows morphological overlap with both squamous intraepithelial lesions (SIL) and adenocarcinoma in situ (AIS)
Essential features
  • SMILE often coexists with other preinvasive lesions, including SIL (up to 93% of cases) and AIS (up to 42% of cases) as well as invasive carcinoma (up to 10% of cases)
  • May be a morphologic indicator of phenotype instability / ambiguity
  • Recently proposed to be a precursor to a unique invasive cervical carcinoma termed "invasive stratified mucin producing carcinoma" (Am J Surg Pathol 2016;40:262)
    • Mucoepidermoid carcinoma is the principal differential diagnosis of this invasive counterpart
Case reports
Microscopic (histologic) description
  • Multilayered and stratified cells (resembling SIL) with intracytoplasmic mucin or cytoplasmic vacuoles throughout the thickness of the lesional epithelium
  • Associated nuclear pleomorphism, hyperchromasia, mitotic activity and apoptotic bodies
    • Most consistent feature is the spacing of nuclei by intracytoplasmic mucin
    • Rounded or lobular contour seen at epithelial stromal interface (in keeping with an in situ lesion)
    • Overt gland formation not seen (as opposed to AIS)
Microscopic (histologic) images

Images hosted on other servers:
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Resembles HSIL but with abundant mucin

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Adenocarcinoma in situ stratified type

Cytology description
  • Jagged group borders
  • Moderate crowding within cell groups
  • Distinct and sharp cytoplasmic borders
  • Spherical nuclear shape
  • Moderate to marked nuclear membrane irregularity
  • Fine granular chromatin structure
    • Cytologic features of SMILE and AIS overlap, however prominent nucleoli and feathering are not typically described in SMILE (Diagn Cytopathol 2016;44:20)
Positive stains
  • Ki67 / MIB1: high index (no threshold stablished)
  • p16: block type staining (full thickness strong nuclear and cytoplasmic staining spanning a continuous segment of abnormal epithelium)
  • Mucicarmine: positive (pink) intracytoplasmic staining
Negative stains
  • Keratins 5 / 14 (may be positive in basal portion of the lesion)
  • p63 (may be positive in basal portion of the lesion, absent in areas of columnar differentiation)
  • IMP3
Differential diagnosis
  • Adenocarcinoma in situ (AIS):
    • Has gland formation; subtle stratification may exist but epithelium retains a columnar shape and lacks the "squamoid" pattern of stratification of SMILE
  • Atypical immature squamous metaplasia:
    • Preserved cell polarity, rare mitoses confined to basal layer, lack of mucin
  • Squamous intraepithelial lesion (SIL):
    • Stratified epithelium with a squamous appearance (polygonal cells with intercellular bridges, lack of intracytoplasmic mucin)
    • As a pitfall, mucin may be present superficially if the SIL colonizes endocervical epithelium (which is usually pushed towards the luminal aspect)
    • In this setting, mucin containing epithelium is benign (no nuclear enlargement, hyperchromasia or mitotic activity) and p16 will be negative in the mucinous cells (staining of the basal aspect colonized by dysplastic squamous epithelium)
Board review style question #1
Which is of the following staining profiles would be expected for SMILE?

  1. Ki67 high, block p16, mucicarmine+, IMP3-, CK14-
  2. Ki67 high, block p16, mucicarmine-, IMP3-, CK14+
  3. Ki67 low, block p16, mucicarmine+, IMP-, CK14-
  4. Ki67 low, block p16, mucicarmine-, IMP+, CK14+
Board review style answer #1
A. SMILE has a high MIB1 index, block staining for p16 and is positive for mucicarmine.
  • SMILE is negative for IMP3 and CK14
  • Both HSIL and AIS stain strongly and diffusely with p16 and tend to have an elevated MIB1 index
  • Mucicarmine is positive in AIS and should be not positive in HSIL
  • IMP3 has been shown to be positive in AIS

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Reference: SMILE (stratified mucin producing intraepithelial lesions)
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