ORIGINAL RESEARCH ARTICLE: CERVIX AND HPV

Cervical Stratified Mucin-Producing Intraepithelial Lesion:

A Systematic Review of Diagnosis and Management
Jennifer L. Wolf, MD,1 Caroline C. Billingsley, MD,2 Ady Kendler, MD, PhD,3 and Amanda L. Jackson, MD2
an invasive form has also been identified.6,7,11 The following case was
Objectives: The aims of the study were to synthesize reported associa- the inspiration for this review and highlights the typical presentation.
tions of stratified mucin-producing intraepithelial lesion (SMILE) of the A 33-year-old G5P3023 African American woman with 5-year
cervix with other dysplasia lesions and immunohistochemical (IHC) stains, smoking history presented for colposcopy secondary to low-grade
compare expected patterns of IHC staining to other lesions in the differen- intraepithelial lesion (LSIL) and positive human papillomavirus
tial diagnosis, and assess follow-up pathology. (HPV) Pap test. Cervical biopsy pathology was consistent with
Methods: This systematic review includes all case reports and case series cervical intraepithelial neoplasia 3 (CIN 3), and she subsequently
of cervical lesions consistent with SMILE based on the histologic diagnosis underwent cold-knife conization (CKC). Pathology on conization
described in the original case series. MEDLINE, EMBASE, and Cochrane was consistent with CIN 3 and SMILE (see Figure 1). Scattered
Database were searched through June 2019. Immunohistochemical analysis, dysplastic cells within the epithelium had a squamous, metaplastic
concurrent lesions, and pathology on follow-up were compiled for compar-
Downloaded from http://journals.lww.com/jlgtd by BhDMf5ePHKbH4TTImqenVBMHby7N9qoLotRTJiM6Jo/AgzBJmyzAxG9/2qXESPL8 on 07/09/2020

appearance, and the areas of HSIL and SMILE stained positive for
ison. Weighted averages of concurrent lesions were calculated. p16. The endocervical curettage was positive for a small focus of
Results: Nine case reports and case series were included, published be- dysplastic squamous epithelium, favoring LSIL. The case was re-
tween 2000 and 2019. Of 9 studies, 6 and 5 studies reported strong, diffuse viewed at multidisciplinary conference, and, as the patient had
staining of p16 and increased expression of Ki-67, respectively. Stratified completed her childbearing, definitive surgical management
mucin-producing intraepithelial lesion is associated with human papillomavi- with hysterectomy was recommended. She underwent total ro-
rus, especially type 18. The weighted average risk of concurrent high-grade botic hysterectomy with bilateral salpingectomy, and final pathol-
squamous intraepithelial lesion was 79% (range = 33%–93%), adenocarci- ogy did not reveal any high-grade dysplasia, AIS, or malignancy.
noma in situ 39% (2.9%–92%), adenocarcinoma 5% (1%–25%), and squa- There is a paucity of published resources on the diagnosis,
mous cell carcinoma 6% (0%–11%). Patients underwent follow-up ranging evaluation, and management of cervical SMILE. Although there
from repeat Pap to radical hysterectomy, with pathology on follow-up in- has been increasing focus on SMILE and its invasive counterpart
frequently and irregularly reported. among the pathology community, it has not yet become widely
Conclusions: Stratified mucin-producing intraepithelial lesion is a rare discussed among gynecologists. The general gynecologist is respon-
lesion with a paucity of research on necessary cytology and IHC stains for sible for reviewing results from Pap smears, colposcopy biopsies,
diagnosis, but p16 and Ki-67 IHC stains can be performed to rule out benign and loop electrosurgical excision procedure (LEEP)/CKC speci-
lesions. The lesion is associated with high risk of concurrent high-grade mens, and as such should be familiar with the diagnosis, diagnos-
squamous intraepithelial lesion, adenocarcinoma in situ, and invasive car- tic criteria, and management of cervical SMILE. In this systematic
cinoma, but studies on the risk of pursuing fertility-preserving manage- review, we sought to compile the case reports available, synthesize
ment are needed. reported association with other dysplasia lesions and immunohisto-
Key Words: cervical dysplasia, adenocarcinoma in situ, chemical (IHC) stains pertinent to diagnosis of SMILE, compare
immunohistochemistry, human papillomavirus expected patterns of IHC staining for SMILE to other lesions in
the differential diagnosis, and compare follow-up pathology to ex-
(J Low Genit Tract Dis 2020;24: 259–264)
plore management recommendations.

S tratified mucin-producing intraepithelial lesion (SMILE) of

the cervix was first reported in 2000 as a premalignant cervi-
cal lesion with features consistent with both high-grade squamous
METHODS
intraepithelial lesions (HSIL) and adenocarcinoma in situ (AIS).1 Eligibility Criteria and Search Strategy
Throughout the ensuing case reports, the histologic features have
consistently been described as stratified epithelium with mucin We conducted a systematic literature review according to the
present throughout the full epithelial thickness but present in the Preferred Reporting Items for Systematic Reviews and Meta-
cytoplasm, not contained in goblet cells.1–9 In 2014, the World Analyses (PRISMA) 2009 guidelines12 and searched MEDLINE,
Health Organization updated its classification system for cervical EMBASE, and Cochrane Database up to June 2019, without limits or
dysplasia to include SMILE as a variant of AIS,10 and since then, language restriction. The following key words/phrases and Medical
Subject Heading terms alone or in combination were used to identify
potentially relevant studies: “stratified mucin-producing intraepithe-
1
Department of Obstetrics and Gynecology, University of Cincinnati Medical lial lesion,” “uterine cervical dysplasia,” “cervical dysplasia,” and
Center, Cincinnati, OH; 2Department of Gynecologic Oncology, University of “mucin.” We included original articles, systematic reviews, and
Cincinnati Medical Center, Cincinnati, OH; and 3Department of Pathology, conference abstracts. Conference abstracts were reviewed for con-
University of Cincinnati Medical Center, Cincinnati, OH
Reprint requests to: Jennifer Wolf, MD, Department of Obstetrics and sistency of associations of SMILE with other lesions and IHC
Gynecology, 231 Albert Sabin Way Rm 4461, Cincinnati, OH 45267. staining but were not included in the final case report compilation
E-mail: [email protected] table because of concern for duplication. Consent was obtained
The authors have declared they have no conflicts of interest. from the patient whose presentation inspired this review.
This study does not meet the definition of human subjects research and does not
require institutional review board approval.
Supplemental digital content is available for this article. Direct URL citations Study Selection
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s Web site (www.jlgtd.com).
Case reports and case series were included if they reported on
© 2020, ASCCP case(s) of SMILE. Cases were compiled regardless of number of
DOI: 10.1097/LGT.0000000000000536 cases or country of origin, but only articles in English were reviewed.

Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020 259

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Wolf et al. Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020

FIGURE 1. Cervical conization pathology with features characteristic of cervical SMILE: atypical nuclei and intracytoplasmic mucin present
(unstained) throughout all layers of the epithelium (hematoxylin and eosin, 200); diffuse and strong p16 stain (inset, 400).

A diagnosis of SMILE was defined based on the histologic descrip- Histology

tion found in the original report by Park et al.1 The search process and The cytologic features described in the seminal case series by
study selection, in concordance with PRISMA guidelines, is illus- Park et al.1 and portrayed throughout the subsequent cases2–9 in-
trated in Figure 2. clude features characteristic of both squamous and glandular dys-
plasia. The stratified epithelium is similar to high-grade CIN in
Data Extraction and Assessment of Risk of Bias that the abnormal nuclei (high nucleus:cytoplasm ratio, nuclear
The Joanna Briggs Institute Critical Appraisal Checklist for hyperchromasia, indistinct nucleoli) are spread throughout the ep-
Case Series13 was used to determine the risk of bias for each study. ithelial layers. However, more consistent with a glandular lesion,
The Joanna Briggs Institute Checklist includes 10 items pertinent cytoplasmic mucin is also present in all the layers and can be seen
to a case series. Two of the 10 items were removed, as they were as discrete vacuoles or cytoplasmic clearing, but the authors do com-
not pertinent to this review. The question of the validity for iden- ment that the mucin may be subtle and only seen with a mucicarmine
tifying cases was discarded, as there is not yet a standard method stain. Specifically, distinct glands are not seen in SMILE. The
for diagnosis of SMILE and the question is one to be addressed by epithelial-stromal interface is rounded, and the final distinguishing
this review. The question of whether the statistical analysis was ap- feature is location at the transformation zone, which aligns with
propriate was also discarded as the case series and reports were the theory that SMILE arises from the reserve cells here.1
observational and reports of percentages of populations. Compila-
tion of risk assessment is available in Supplemental Table 1, http:// Incidence of SMILE
links.lww.com/LGT/A157. Two of the case series addressed the incidence of SMILE.
Boyle and McCluggage4 extrapolated an incidence rate of 0.6%
Data Synthesis based on the number of cervical specimens with SMILE for a
Immunohistochemical staining patterns of SMILE found 6-year period compared with the total number of cervical speci-
within each case report or case series was noted and compiled mens received by their center over that same period. Onishi et al.7
for comparison. The reported concurrent lesions (HSIL, AIS, ad- reported an incidence of 2.7%; however, this is taken from a pop-
enocarcinoma, squamous cell carcinoma, and invasive stratified ulation of HSIL or carcinoma (excluding low-grade dysplasia or
mucin-producing carcinoma [ISMC]) for each case series was re- benign specimens).
corded along with the number of cases and a weighted average
was calculated using Excel. The range of estimated concurrence Immunohistochemical Analysis
of lesions was also compiled and graphed. Among the 9 case reports and case series, a variety of IHC
stains were used for diagnosis of SMILE. The most commonly
tested included p16 and Ki-67. Other stains were used less consis-
RESULTS tently. Table 2 summarizes the stains and interreport variability of
any staining patterns.
Study Characteristics The differential diagnosis when considering SMILE includes
Three case reports and 6 case series were found, case series immature squamous metaplasia and tubo-endometrial metaplasia
ranging from presentation of 12–69 cases and spanning from (TEM), in addition to CIN or AIS alone.1,18 Immature squamous
2000 (original Park et al.1 article published) to 2019. Study char- metaplasia typically contains mucin that is confined to the surface
acteristics of all 9 included studies are presented in Table 1. Three layer, whereas mucin is found throughout the full thickness in
studies originated in the United States, 2 were from Japan, and the SMILE.4 Tubo-endometrial metaplasia is a reparative response
remaining studies were conducted in South Korea, Northern Ireland, secondary to prior cautery, such as a previous LEEP. However, this
Western Australia, and Canada. Case series were either collected via lesion is typically found to have a mixture of ciliated and nonciliated
retrospective review of a cohort of cervical biopsies with SMILE cells and is only focally positive for p16 and Ki-67,18,19 whereas
diagnosis or through review of author departments' available pa- SMILE exhibits diffuse staining of p16 and expresses Ki-67 through-
thology, selecting cases with SMILE cytologic features. out the full thickness.

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Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020 Cervical SMILE

FIGURE 2. Overview of steps taken in the systematic literature review (PRISMA flowchart).

Human Papillomavirus associated with AIS. Nine cases involved co-existing invasive car-
Although p16 is a marker for general oncogenic HPV infec- cinoma, both squamous and glandular. Since the original report,
tion, the specific type of HPV also portends important predictive studies have estimated that SMILE is associated with concurrent
information. The pathogenesis of progression from low-grade HSIL in 79% (weighted average; range = 33%–93%) of cases,
dysplasia to invasive squamous carcinoma is associated with per- AIS in 39% (2.9%–92%) of cases, adenocarcinoma in 5% (1%–
sistent HPV infection, especially HPV 16, whereas adenocarci- 25%) of cases, and squamous cell carcinoma in 6% (0%–11%)
noma is more associated with HPV 18.10 Two of the case series of cases, graphically depicted in Figure 3. In 2016, an invasive var-
addressed this. Schwock et al.8 found that SMILE lesions were iant of SMILE was described and has since been included in 3
positive for HPV in all cases, 33% HPV 16, 58% HPV 18, and case series.6,7,11
33% “other.” Fukui et al.9 further categorized HPV typing into
the 2 species of HPV, alpha-9 (HPV 16, 31, 33, 35, 52, and 58) Invasive SMILE
and alpha-7 (HPV 18, 39, 45, 59, and 68), postulating that the Stratified mucin-producing intraepithelial lesion is a prema-
“other” types of high-risk HPV could be further used for classifi- lignant lesion, and in addition to being associated with other pre-
cation of risk. The HSIL area of the reported case's cervical biopsy malignant and malignant lesions, there is also an invasive variant
was positive for HPV 52 (alpha-9) and the SMILE area was pos- of SMILE itself. Lastra et al.6 were the first to identify this during
itive for HPV 68 (alpha-7). review of institutional archives where they found cases containing
the morphology of SMILE and invasive features, termed ISMC or
i-SMILE. In 2019, Horn et al.11 published a case series of 5 previ-
Concurrent Lesions ously diagnosed adenocarcinomas from their institution that were
The original 2,000 case series1 described 18 cases of SMILE, reclassified as i-SMILE and reviewed available cases from
14 of which were associated with CIN 2–3 and 11 of which were Lastra et al.,6 Onishi et al.,7 and their institution. The lesion is

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Wolf et al. Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020

TABLE 1. Characteristics of Case Reports and Case Series on SMILE

Author No. cases included Source of cases Country of study

1
Park et al. (2000) 18 Review of (1) consultation files, (2) database United States
of previous cases diagnosed as both CIN
and AIS, and (3) previously reported
series of adenocarcinomas.
Report of only cases with SMILE cytology.
Cha et al.2 (2012) 1 Single case South Korea
Goyal et al.3 (2014) 1 Single case United States
Boyle and McCluggage4 (2015) 69 Retrospective analysis of pathology reports Northern Ireland
with a diagnosis of SMILE on cervical punch
biopsies and resection specimens 5/2008-4/2014
Backhouse et al.5 (2015) 34 Cases of SMILE diagnosed between 2005 and Western Australia
2014 in which a conventional Pap smear taken
within the preceding 12 mo was available for review
Lastra et al.6 (2016) 15 Retrospective search of multiple institutional United States
archives for SMILE
Reviewed slides for 18 cases—15 consistent
with cytology upon review. 7 SMILE, 8 ISMC
Onishi et al.7 (2016) 12 Retrospective review of specimens obtained from Japan
445 patients with HSIL, AIS, SMILE, or
invasive carcinoma from 2004–2014.
56% intraepithelial lesions, 44% invasive carcinomas
Schwock et al.8 (2016) 13 Retrospective review of 2 tertiary care centers Canada
from 2000 to 2014 for LEEP and CKC
specimens with SMILE
Cases with invasive carcinoma excluded
Fukui et al.9 (2019) 1 Single case Japan

described on gross pathology as a polypoid and exophytic mass found. Hysterectomy is the preferred treatment for women who
and histologically features a finger-like pattern of invasion with have completed childbearing. For those who desire retained fertil-
an inflammatory response surrounding the tumor consisting of pre- ity and if margins or endocervical curettage are involved in the
dominantly neutrophils. Patients with stage IA disease were ex- cervical conization specimen, re-excision is preferred over close
cluded from the review, but the remaining cases were diagnosed interval follow-up.10,20 The cases reviewed had obtained initial
with a mean tumor size of 4.0 cm, and 8 of the 13 cases experienced pathology from all types of cervical specimens, as seen in Table 3.
recurrence between 6 weeks and 36 months from surgery. All of the The provided follow-up was often unknown. No case reports or
cases were obtained through retrospective review and reclassifica- case series recorded patients' future fertility plans.
tion, and all but one had been treated with radical hysterectomy.
The mean age at diagnosis for SMILE without invasive lesions DISCUSSION
was 28.9 and 36.7 and for SMILE with invasive components or
associated invasive lesions was 44.1 and 47.1 in the Lastra et al.6 Although SMILE was officially categorized as a variant of
and Onishi et al.7 case series, respectively, consistent with pro- AIS in 2014, the diagnosis and management still seem to be highly
gression from premalignant to malignant disease for 10–15 years. individualized by practitioners. Although the cytologic features
of SMILE are consistently described across the literature, SMILE
has often been classified as purely squamous or glandular in the
Management past and the diagnostic challenge lies in the overlay of features
Per the World Health Organization 2014 Guidelines, the man- and especially the mucin distribution, which has been described
agement of SMILE is recommended to be the same as if AIS were as difficult to visualize on typical hematoxylin and eosin stains.

TABLE 2. Immunohistochemical Staining Pattern of SMILE

IHC stain Marker/purpose Pattern No. studies supporting Interstudy variability

14
p16 Dysplastic HPV effect ++ 6 None
Ki-6714 Cell proliferation ↑ 5 None
p6315 Squamous epithelium −/+ 3 None
Mucicarmine Epithelial mucin ++ 2 None
CK7/CAM5.214 Glandular epithelium ++ 2 None
IMP316 Progression benign to invasive carcinomas −, −/+ 2 Yes
CK1414 Squamous epithelium − 1 NA
Bcl-217 Inhibit apoptosis (oncoprotein) − 1 NA
++, diffusely positive stain; +/−, focal positive stain; −, negative stain; ↑, increased expression; NA, not applicable.

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Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020 Cervical SMILE

FIGURE 3. Rate of concurrent lesions with SMILE. Vertical lines represent the range of percent lesions concurrently found in SMILE in the case
reports/series reviewed; solid squares represent weighted average of the rate of finding each concurrent lesion with SMILE. ISMC, invasive
stratified mucin-producing carcinoma; SCC, squamous cell carcinoma.

Various IHC stains have been used by different institutions. The were routine for that institution or if they were needed for clarifi-
LAST Project determined that there were not enough data for a cation of the diagnosis by the pathologist. If additional stains are
recommendation for any biomarker other than p16,21 and among to be used in the future, a study uniformly applying these stains
the reviewed series here, only 2 IHC markers were used consistently to benign and premalignant specimens would need to demonstrate
(p16 and Ki-67). Their expression is identical between HSIL, AIS, benefit in making the diagnosis.
invasive adenocarcinoma, and SMILE and thus are most useful in dif- Stratified mucin-producing intraepithelial lesion is associated
ferentiating SMILE from benign lesions such as squamous metapla- with other concurrent lesions, especially a high rate of concurrent
sia or TEM, to spare a patient an invasive procedure if the HSIL and AIS, and can progress to an invasive carcinoma.
diagnosis is in question. As all of the case series were retrospec- The reviewed case series were limited by the method of collection
tive, it is unclear if additional stains were performed because they of specimens, many drawn from a pool of high-grade squamous

TABLE 3. Management of SMILE in Case Reports and Case Series

Author Pathology source Follow-up

1
Park et al. (2000) Unclear biopsy source Not provided
Cha et al.2 (2012) CKC Hysterectomy, no residual tumor
Goyal et al.3 (2014) Cervical biopsy LEEP (SMILE, negative margins),
hysterectomy (no residual tumor)
Boyle and McCluggage4 (2015) Cervical biopsy, LEEP Not provided
Backhouse et al.5 (2015) Cervical biopsy, LEEP, CKC 2 cervical biopsies with follow-up LEEP and
CKC negative for SMILE.
Otherwise, not provided.
Lastra et al.6 (2016) Cervical biopsy, cone biopsy, hysterectomy 7 SMILE cases: 3 unknown, 2 repeat pap
(ASCUS HPV neg; NILM), 2 repeat
cone biopsies (LSIL; SMILE + HSIL)
8 ISMC: 4 unknown, 1 radical hysterectomy
(AIS); 1 chemotherapy/radiation, 1 death,
1 biopsy of lung metastasis
Onishi et al.7 (2016) Excluded cervical biopsies, 11 hysterectomy, 1 cone biopsy,
otherwise unclear biopsy source 5 chemotherapy/radiation
Schwock et al.8 (2016) LEEP, CKC Not provided
Fukui et al.9 (2019) Cervical biopsy Cone biopsy and f/u pap (no abnormal cytology)
ASCUS, atypical squamous cells of undetermined significance; NILM, negative for intraepithelial lesion or malignancy.

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Wolf et al. Journal of Lower Genital Tract Disease • Volume 24, Number 3, July 2020

and glandular lesions instead of the general population, given its 15 cases presenting a spectrum of cervical neoplasia with description
rarity. Although the rate of concurrent lesions diagnosed on orig- of a distinctive variant of invasive adenocarcinoma. Am J Surg Pathol 2016;
inal pathology is interesting, there was scant information on pa- 40:262–9.
thology of follow-up specimens. Of this available information, 7. Onishi J, Sato Y, Sawaguchi A, et al. Stratified mucin-producing intraepithelial
no cases included additional lesions that were not diagnosed on lesion with invasive carcinoma: 12 cases with immunohistochemical and
original pathology. For AIS, the data are clear: a large cohort study ultrastructural findings. Hum Pathol 2016;55:174–81.
conducted at MD Anderson calculates the risk of residual AIS to 8. Schwock J, Ko HM, Dubé V, et al. Stratified mucin-producing
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be 2.8%, and recurrent AIS if fertility preservation is undertaken Cytol 2016;60:225–31.
to be 2.0%.14 The risk of residual, previously undiagnosed, and re-
9. Fukui S, Nagasaka K, Iimura N, et al. Detection of HPV RNA molecules in
current lesions is assumed to be equivalent to AIS given similar stratified mucin-producing intraepithelial lesion (SMILE) with concurrent
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before carcinoma,6,7,11 but a similarly designed study would be
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Classification of Tumours of Female Reproductive Organs. Lyon: IARC
Press; 2014.
Limitations
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In addition to the limitations noted previously, there is a pau-
systematic reviews and meta-analyses: the PRISMA statement. PLoS Med
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2009;7:889–96.
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cluded ethnicities. The geographic regions were assumed based 12. Moola S, Munn Z, Tufanaru C, et al. Systemmatic reviews of etiology and
on the authors' countries of publication, but it is difficult to make risk. In: Aromataris E, Munn Z, eds. Joanna Briggs Institute Reviewer's
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