Stratified Mucin-producing Intraepithelial Lesion Research Articles

Benign stratified intraepithelial mucinous proliferation of the uterine cervix: Significance of a previously unreported potential mimic of SMILE

Stratified mucin-producing intraepithelial lesion (SMILE) is a histologic subtype of HPV-associated endocervical adenocarcinoma in situ. We have observed benign endocervical changes resembling SMILE. We aim to characterize this pattern and explore its potential association with dysplasia. We retrospectively retrieved all 296 consecutive cases accessioned as endocervical biopsies. Some included multiple specimens, totaling 483 biopsies and 219 endocervical curettages (ECC), n = 702. We included cases showing endocervical epithelial stratification often with pencillate (triangular-shaped) nuclei. We rejected cases in which layering represented tangential sectioning, metaplasia, microglandular hyperplasia, gastric type epithelial changes, and dysplasia. We found benign stratified intraepithelial mucinous proliferation in 51 patients, either with a multilayered (n = 27) or a two-layered appearance (n = 24). Overall, multilayered proliferation occurred in 6 % (29/483) of biopsies and in 0.9 % of ECCs (2/219). Two-layering was identified in 4 % of all biopsies (20/482) and was not seen in ECCs. Histologic findings included stratification, intracytoplasmic mucin, paler cytoplasm, low nuclear-to-cytoplasmic ratio, often pencillate nuclei, rare mitoses, and no apoptotic bodies. P16 immunohistochemistry (n = 12) was negative, suggesting absence of underlying high-risk HPV infection. HSIL was concomitant in 29.6 % (8/27) of patients with multilayered proliferation. Concurrent SMILE was not observed. We also reviewed 13 SMILE cases. Concurrent multilayered benign proliferation was identified in 54 % (7/13) of cases. We describe benign stratified intraepithelial mucinous proliferation of the cervix, which morphologically may overlap with SMILE. Its presence in most SMILE cases suggests a potential relationship. The multilayered form represents a diagnostic pitfall when mitotically active. Because of the often-coexistent HSIL, we propose that its presence should prompt scrutiny to rule out any associated dysplasia.

Invasive stratified mucin-producing carcinoma (ISMC) of uterine cervix: description of pathological findings and prognosis factors in a series of 15 Chinese patients.

Invasive stratified mucin-producing carcinoma (ISMC), an invasive form of stratified mucin-producing intraepithelial lesion (SMILE), is a newly named human papillomavirus (HPV) associated mucous adenocarcinoma of cervix. We aim to provide more clinical and pathological data for this uncommon disease. Fifteen cases diagnosed as ISMC in our hospital were included, and their clinical and pathological data were retrospectively analyzed. The patients' median age was 43years (range, 30-54years). The most prevalent symptom was abnormal vaginal bleeding. HPV test indicated high-risk HPV in all of our 15 cases. In addition, we observed several other architectural patterns of ISMC, including nest, gland-forming or lumen-forming, papillary with extravasated pools of mucin and solid. Immunohistochemically, all of our ISMC cases showed block-like expression of P16 and diffuse positive expression of CK8 and CK18, while P63, P40 and CK5/6 were spotted positive, or completely negative. Most importantly, ISMC has a relatively high lymph node metastasis rate of 33%. ISMC is a special type of HPV-associated adenocarcinoma, displaying a wide morphologic spectrum combined with a unique immunohistochemical profile. Clinically, ISMC may have a higher rate of lymph node metastasis, which suggests more attention to postoperative follow-up.

Stratified Mucin-Producing Intraepithelial Lesion (SMILE) of the Uterine Cervix: High-Risk HPV Genotype Predominance and p40 Immunophenotype.

Stratified mucin-producing intraepithelial lesion (SMILE) is a rare high-grade cervical precancerous lesion designated a variant of adenocarcinoma in situ (AIS) in the WHO classification. We aimed to determine HPV genotypes, immunohistochemical phenotype and mucin presence in SMILE. Between 2010 and 2018, SMILE was diagnosed in 34 out of 6958 (0.5%) cervical biopsies, in 23 patients. Twenty-six tissue samples from twenty-one patients were available for further analysis, including 13 with SMILE alone, 12 with SIL and/or AIS and one with HSIL, AIS and endocervical adenocarcinoma. HPV genotyping was performed using the Seegene Anyplex II HPV 28 assay. Of the 26 samples, a single HPV genotype was identified in the majority of cases (n = 22), including 12/13 SMILEs associated with SIL/AIS. All but one were high-risk HPV genotypes (23/24; 96.8%). We identified seven different HPV genotypes, the most common being HPV16 (n = 10; 43.5%), HPV18 (n = 8, 34.8%) and HPV 31 (n = 5, 21.7%). All SMILEs showed a strong positive reaction to p16, CK7, CK19 and high Ki67 expression comparable to adjacent HSIL and/or AIS if present. SMILE showed variable mucin presence and p40-positive squamous differentiation suggesting phenotypic diversity in cervical precancerous lesions infected by single HPV.

Invasive Stratified Mucin-Producing Carcinoma (ISMC) of the uterine cervix: An analysis of 6 cases with distinctive clinicopathological features

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described histologic variant of high-risk human papillomavirus (HPV)-associated endocervical adenocarcinoma, as the putative invasive counterpart of the stratified mucin-producing intraepithelial lesion (SMILE). ISMC can display variable architectural patterns and usually coexists with other more conventional types of HPV-associated carcinomas, which makes diagnosis and differential diagnosis of ISMC is difficult for pathologists. Moreover, the prognosis of ISMC is still controversial. We analyzed 6 ISMCs with detailed pathological and clinical information. Intraepithelial lesion, including 1 high-grade squamous intraepithelial lesion and 1 SMILE, was found. Various architectures were observed (including nest, glandular, solid, trabecular, and single cell). Nuclear peripheral palisading, apoptotic bodies and mitoses, and variable cytoplasmic mucin vacuoles were seen in all of our cases. The predominance of neutrophils infiltration was seen in only 1 tumor. All the tumors infiltrated the cervical stroma in Silva pattern C manner. p63 and/or p40 was characteristically expressed in the peripheral cells in only 2 cases. High-risk HPV infection was observed in 3/3 detected cases. All the patients were alive during the follow-up time. Recognition of this infrequent tumor may help pathologists and oncologists for an accurate diagnosis and a better understanding of the clinicopathological behavior.

Stratified Mucin Producing Intraepithelial Lesion (SMILE): Report of Two Cases

Abstract Introduction/Objective Stratified mucin producing intraepithelial lesion (SMILE) is an uncommon variant of adenocarcinoma in-situ (AIS), often confused with immature squamous metaplasia or high-grade intraepithelial lesion (HG-SIL). This premalignant lesion is often found in proximity to HG-SIL, AIS and invasive carcinomas. SMILE is also a precursor for Invasive Stratified Mucinous Carcinoma. As was first described in the original article, SMILE lesions are considered derived from the reserve cells at the transformation zone where HPV infections lead to varied phenotypes. Methods Two cases of SMILE were collected from our files. A 31-year-old female with a previous abnormal Pap smear result. She underwent cervical biopsy and subsequent LEEP.The second patient, a 26-year-old female, underwent a cervical biopsy after an abnormal Pap smear. Results Histologically, stratified cells with presence of conspicuous mucin production with abundant cytoplasm separating cells in mid and lower layer of epithelium accompanied with conspicuous spacing of nuclei in the lower to middle epithelial layer are seen. Additionally, there is nuclear pleomorphism with absence of gland formation. Mucicarmine stain was performed and showed positive staining in mucin producing dysplastic cells throughout the epithelium. Immunoperoxidase stains demonstrated positivity for p16 (nuclear and cytoplasmic) and p63 in the basal cells. The Ki67 proliferation index was high (approximately 90%). These results supported the diagnostic interpretation of SMILE. Conclusion SMILE is a rare variant of glandular precursor lesion in the cervix. It is frequently associated with HG-SIL and/or AIS, but may rarely appear as an isolated finding. The differential diagnosis include adenocarcinoma in-situ, atypical immature squamous metaplasia and squamous intraepithelial lesion. Since these lesions are cervical glandular intraepithelial neoplasms, the morphologic recognition of a SMILE in a biopsy is important for patient follow up, particularly in cases were only squamous intraepithelial lesion is present in the sample.

Is hysterectomy necessary for the treatment of stratified mucin-producing intraepithelial lesions (SMILE) of the cervix?

Objective: Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon premalignant cervical intraepithelial lesion characterized by histopathologic features resembling those observed in HSIL and AIS. Because of its hybrid morphology, there is no consensus as to the most appropriate category for this lesion and it poses a pathologic challenge with no specific management guidelines.

The Evolving Spectrum of Precursor Lesions of Cervical Adenocarcinomas.

Modern classification schemes divide cervical adenocarcinomas into human papillomavirus (HPV)-associated and HPV-independent types. The precursor lesions of the former are well known and comprise HPV-associated (usual/endocervical) adenocarcinoma in situ (AIS) and the much less common stratified mucin-producing intraepithelial lesion (SMILE). The precursor lesions of HPV-independent cervical adenocarcinomas are much less well known, although postulated precursors of gastric-type adenocarcinoma include atypical lobular endocervical glandular hyperplasia and gastric-type AIS. In this review, we cover HPV-associated and HPV-independent precursor lesions of cervical adenocarcinomas concentrating on diagnostic criteria (morphology and immunophenotype) and differential diagnosis. We propose a uniform terminology and diagnostic criteria for precursor lesions showing intestinal differentiation with goblet cells because this may be a feature of both HPV-associated and HPV-independent AIS.

Cervical Stratified Mucin-Producing Intraepithelial Lesion: A Systematic Review of Diagnosis and Management.

The aims of the study were to synthesize reported associations of stratified mucin-producing intraepithelial lesion (SMILE) of the cervix with other dysplasia lesions and immunohistochemical (IHC) stains, compare expected patterns of IHC staining to other lesions in the differential diagnosis, and assess follow-up pathology. This systematic review includes all case reports and case series of cervical lesions consistent with SMILE based on the histologic diagnosis described in the original case series. MEDLINE, EMBASE, and Cochrane Database were searched through June 2019. Immunohistochemical analysis, concurrent lesions, and pathology on follow-up were compiled for comparison. Weighted averages of concurrent lesions were calculated. Nine case reports and case series were included, published between 2000 and 2019. Of 9 studies, 6 and 5 studies reported strong, diffuse staining of p16 and increased expression of Ki-67, respectively. Stratified mucin-producing intraepithelial lesion is associated with human papillomavirus, especially type 18. The weighted average risk of concurrent high-grade squamous intraepithelial lesion was 79% (range = 33%-93%), adenocarcinoma in situ 39% (2.9%-92%), adenocarcinoma 5% (1%-25%), and squamous cell carcinoma 6% (0%-11%). Patients underwent follow-up ranging from repeat Pap to radical hysterectomy, with pathology on follow-up infrequently and irregularly reported. Stratified mucin-producing intraepithelial lesion is a rare lesion with a paucity of research on necessary cytology and IHC stains for diagnosis, but p16 and Ki-67 IHC stains can be performed to rule out benign lesions. The lesion is associated with high risk of concurrent high-grade squamous intraepithelial lesion, adenocarcinoma in situ, and invasive carcinoma, but studies on the risk of pursuing fertility-preserving management are needed.

Invasive Stratified Mucin-producing Carcinoma (ISMC) of the Cervix: A Study on Morphologic Diversity.

Invasive stratified mucin-producing carcinoma (ISMC) is a recently described tumor with similar morphology to the stratified mucin-producing intraepithelial lesion. Stratified mucin-producing intraepithelial lesion and ISMC likely arise from human papillomavirus (HPV)-infected reserve cells in the cervical transformation zone that retain their pluripotential ability to differentiate into various architectural and cytologic patterns. This is important, as small studies have suggested that ISMC may be a morphologic pattern associated with more aggressive behavior than usual HPV-associated adenocarcinoma. We sought to study the morphologic spectrum of this entity and its associations with other, more conventional patterns of HPV-associated carcinomas. Full slide sets from 52 cases of ISMC were reviewed by an international panel of gynecologic pathologists and classified according to the new International Endocervical Criteria and Classification system. Tumors were categorized as ISMC if they demonstrated stromal invasion by solid nests of neoplastic cells with at least focal areas of mucin stratified throughout the entire thickness, as opposed to conventional tall columnar cells with luminal gland formation. Tumors comprising pure ISMC, and those mixed with other morphologic patterns, were included in the analysis. Twenty-nine pure ISMCs (56%) and 23 ISMCs mixed with other components (44%) were identified. Other components included 13 cases of usual-type adenocarcinoma, 6 adenosquamous carcinoma, 3 mucinous-type adenocarcinoma, 1 high-grade neuroendocrine carcinoma. ISMC displayed architectural diversity (insular, lumen-forming, solid, papillary, trabecular, micropapillary, single cells) and variable cytologic appearance (eosinophilic cytoplasm, cytoplasmic clearing, histiocytoid features, glassy cell-like features, signet ring-like features, bizarre nuclei, squamoid differentiation). Awareness of the spectrum of morphologies in ISMC is important for accurate and reproducible diagnosis so that future studies to determine the clinical significance of ISMC can be conducted.

Invasive stratified mucin-producing carcinoma. A case series with associated pathological findings

Background: Stratified mucin producing intraepithelial lesion (SMILE) is associated with high risk HPV carcinogenesis and morphologically overlaps with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS). In 2016, Schoolmeester et al.1 described a case series of SMILE in which they observed unambiguous invasive adenocarcinomas resembling SMILE and proposed the term ‘invasive SMILE’ for such lesions. Aims: To describe a case series of a recently named group of endocervical adenocarcinomas. Methods: A retrospective search of the practice records was performed using the last year of records. Eight cases were identified, 3 of which had a component of invasive carcinoma resembling SMILE. Results: We identified 3 cases of invasive SMILE and described their pathological features. Discussion: All cases showed cytologically bland nuclear features and distinct palisading. Mitotic figures and apoptosis were easily identified in all 3 cases. 2 out of 3 cases were mucin rich and showed a neutrophilic infiltrate. One case was mucin poor and lacked a neutrophilic infiltrate. We found co-existent CIN in 66% of cases and ACIS in 33% of cases. There are clear morphological and immunohistochemical features supporting the designation of invasive SMILE as a distinct entity in the spectrum of cervical neoplasias. Reference1.Lastra R, Park J, Schoolmeester K. Invasive stratified mucin-producing carcinoma and stratified mucin-producing intraepithelial lesion (SMILE): 15 cases presenting a spectrum of cervical neoplasia with description of a distinctive variant of invasive adenocarcinoma. Am J Surg Pathol 2016; 40: 262–9.

Clinicopathological features of stratified mucin-producing neoplastic lesions of the cervix

Objective: To investigatethe clinicopathological features of stratified mucin-producing intraepithelial lesion (SMILE) and invasive stratified mucin-producing carcinoma (ISMC) of the cervix with review of the literature. Methods: Sixteen patients with SMILE/ISMC components of the cervix were collected from files in the Department of Pathology at Xijing Hospital from January 2007 to March 2019. Clinicopathological data included age at diagnosis, clinical presentation, histological type, depth of invasion measurement, the status of lymphovascular space invasion (LVSI) and lymph node metastasis, FIGO staging and follow-up. Histochemistry AB and PAS-D staining and immunostaining for cytokeratin (CK) 7, p16, p63, p40, PAX8, MUC6, p53 were performed simultaneously. In addition, twelve cases with invasive endocervical adenocarcinoma were evaluated using three-tiered pattern-based system (also called Pattern Classification). Results: The average age at diagnosis for patients was 49.7 years (range, 33 to 65 years), and vaginal bleeding occurred in the majority of cases (13/16). The characteristic morphology of SMILE and ISMC was present as non-invasive and invasive stratified epithelium that the full-thickness cells contained different amount of cytoplasmic mucin, respectively. Five cases of SMILE coexisted with adenocarcinoma in situ (1 case), high-grade squamous intraepithelial lesion (1 case), and invasive adenocarcinoma (3 cases). Thirteen cases with ISMC components included pure ISMC (3 cases), mixed with usual-type endocervical adenocarcinoma (8 cases) or squamous cell carcinoma (2 cases). All pure ISMC had lymph vascular space invasion and depth of invasion exceeded 10 mm. All eleven cases of invasive adenocarcinoma with ISMC components belonged to Pattern C tumors, which typically showed diffusely destructive stromal invasion, solid or poorly differentiated components. The results of histochemical staining confirmed that SMILE/ISMC cells were rich in acidic and neutral mucin. The immunohistochemical staining for CK7 and p16 was diffusely strong positive in SMILE (4/4) and ISMC (8/8) components. The positive expressions of p63 and p40 was located in peripheral cells of stratified epithelial nests or merely in a few cells of SMILE (1/3) and ISMC (2/8) components. In ISMC tissues, there were partial expression of MUC6 (5/7), focal expression of PAX8 (2/8), and wild-type expression pattern (4/10) or completely negative expression (6/10) of p53 protein. All thirteen patients with follow-up data were alive (mean 50.5 months, range 4 to 140). Conclusions: As new tumor entities, SMILE is a rare and unique endocervical intraepithelial lesion, while ISMC belongs to an invasive leison. Given that the tumors with ISMC components may have aggressive behavior, it is important for clinicians and pathologists to fully understand the clinicopathological features of SMILE and ISMC.

Detection of HPV RNA molecules in stratified mucin-producing intraepithelial lesion (SMILE) with concurrent cervical intraepithelial lesion: a case report

BackgroundStratified mucin-producing intraepithelial lesion (SMILE) is a rare precursor lesion in the uterine cervix that is considered a variant of adenocarcinoma in situ (AIS). Although human papillomavirus (HPV) is thought to be related to the development of SMILE, there is little information available on the detection of HPV integrated into the lesion.Case presentationA 30-year-old female underwent a routine uterine cervical cancer screening, and her Pap smear indicated the possible existence of atypical glandular cells. A cervical biopsy with endocervical curettage was performed. The histopathological analysis showed that she had SMILE and high-grade squamous intraepithelial lesion (HSIL) on her cervix. The lesion was found to be positive for HPV genotypes 52 and 68 by multiplex PCR. In situ hybridization with HPV RNA probes revealed that these HPV types were involved in the onset of HSIL and SMILE, respectively.ConclusionsRare, high-risk HPV genotypes may contribute to the development of SMILE, and their detection can be useful for preventing the progression to carcinoma and ensuring adequate patient management.

Diagnostic Algorithmic Proposal Based on Comprehensive Immunohistochemical Evaluation of 297 Invasive Endocervical Adenocarcinomas.

The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human papilloma virus-associated (HPVA) and non-human papilloma virus-associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion [iSMILE]) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus-associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.

Extramammary Paget disease of the penis closely mimicking the penile analogue of stratified mucin-producing intraepithelial lesion.

Extramammary Paget disease of the penis closely mimicking the penile analogue of stratified mucin-producing intraepithelial lesion.

Stratified mucin-producing intraepithelial lesion (SMILE) associated with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) – a case report

Stratified mucin-producing intraepithelial lesion (SMILE) associated with cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS) – a case report

The morphological and immunohistochemical characteristics of stratified mucin-producing intraepithelial lesion

to analyze archival materials for the detection of SMILE and its subsequent morphological and immunohistochemical characterization. Cervical cone specimens from 53 women with histologically verified CIN3 were examined. The diagnosis of SMILE was based on the positive mucicarmine staining and weak focal expression of p63. The samples containing SMILE were further immunohistochemically examined using the biomarkers P16, Ki-67, Oct4, CD117, CD34, p53, EMA, and CK15. SMILE was detected in 2 of the 53 patients and concurrent with CIN3 in both cases. SMILE was characterized by the stratified arrangement of atypical cells containing mucin, the positive mucicarmine staining of the entire layer of the atypical epithelium, weak focal p63 expression, high Ki-67 expression, and diffuse р16Іnk4а staining. Both SMILE samples showed weak diffuse p53 expression in the presence of single cells with the pronounced nuclear staining pattern for p53 in one female patient. Weak focal CK15 expression was visualized in SMILE. The expression of the stem cell markers Oct4 and CD117 and the angiogenic marker CD34 was absent in the examined cervical epithelial preparations. The diffuse and intense expression of the marker EMA, which was not different from that in the endocervical and stratified squamous epithelium, and CIN3 was established in SMILE. The findings suggest that SMILE is morphologically and immunohistochemically similar to CIN3. In this investigation, these abnormalities differed only in the mucicarmine staining and expression of p63. This may be indicative of the underdiagnosis of SMILE, attendant СIN3 in the routine practice of a clinical pathologist, as the diagnosis of CIN3 is primarily based on the results of assessment of only the preparations stained with hematoxylin and eosin; the expression of p16 and Ki-67 is evaluated in some cases, which fails to differentiate SMILE and CIN3 in a number of preparations. The diagnosis of SMILE can be made only by immunohistochemical examination.

Stratified mucin-producing intraepithelial lesion with invasive carcinoma: 12 cases with immunohistochemical and ultrastructural findings

Stratified mucin-producing intraepithelial lesion (SMILE) is considered to be a variant of adenocarcinoma in situ (defined as intraepithelial malignant glandular epithelium without invasion) or adenosquamous carcinoma in situ of the uterine cervix. However, recent study suggested that SMILE is more similar to high-grade squamous epithelial lesion by their immunohistochemical findings. An invasive form of SMILE "invasive stratified mucin-producing carcinoma (ISMC)" has been also proposed, but immunohistochemical features are not well documented. Therefore, this study aimed to clarify the immunohistochemical characteristics of SMILE and ISMC. Twelve cases of SMILE were found among 445 patients (2.7%) with high-grade intraepithelial lesions or invasive carcinomas, 3 of whom had solely intraepithelial disease with SMILE component (mean age, 37 years; range, 30-48 years) and 9 with invasive carcinomas (mean age, 47 years; range, 37-66 years; including ISMC). Immunohistochemically, SMILE and ISMC were diffusely positive for p16 and CAM5.2, focally for IMP3, and almost negative or only focally positive for p63. Nuclear signals in SMILE and invasive carcinomas were detected by human papillomavirus (HPV) in situ hybridization; 5 cases showed HPV16 and/or HPV18 polymerase chain reaction products. The ultrastructural study of 1 case showed surface microvilli and small vacuolar structure in SMILE; ISMC had mucous-like vacuoles, many mitochondria and intracytoplasmic lumen but lacked tonofilament. These findings were more similar to adenocarcinoma in situ or adenocarcinoma than squamous intraepithelial lesion or squamous cell carcinoma. We suggest that SMILE is an intraepithelial neoplasm and ISMC is an invasive form of SMILE.

Invasive Stratified Mucin-producing Carcinoma and Stratified Mucin-producing Intraepithelial Lesion (SMILE)

Stratified mucin-producing intraepithelial lesion (SMILE) is a cervical intraepithelial lesion, distinct from conventional squamous or glandular counterparts, believed to arise from embryonic cells at the transformation zone by transdifferentiation during high-risk HPV-associated carcinogenesis. It is characterized by stratified, immature epithelial cells displaying varying quantities of intracytoplasmic mucin throughout the majority of the lesional epithelium. We identified a distinct form of invasive cervical carcinoma with morphologic features identical to those in SMILE, which we have termed "invasive stratified mucin-producing carcinoma." Fifteen cases from 15 patients (mean 36 y; range, 22 to 64 y) were retrieved from the pathology archives of multiple institutions with a diagnosis of either SMILE or invasive cervical carcinoma with a description or comment about the invasive tumor's resemblance to SMILE. Seven cases had solely intraepithelial disease with a component of SMILE (mean 29 y; range, 22 to 40 y). The 8 other cases had invasive stratified mucin-producing carcinoma (mean 44; range, 34 to 64 y) in which SMILE was identified in 7. All cases of invasive stratified mucin-producing carcinoma demonstrated stratified, immature nuclei with intracytoplasmic mucin, which morphologically varied between cases from "mucin-rich" to "mucin-poor" in a similar manner to SMILE. All cases had mitotic figures and apoptotic debris, and an intralesional neutrophilic infiltrate was seen in the majority of cases. In cases of invasive carcinoma, the depth of invasion ranged from <1 to 19 mm. Follow-up information was available in 8 cases and ranged from 1 to 36 months (mean 11 mo). Three cases of invasive stratified mucin-producing carcinoma had biopsy or resection-proven metastatic carcinoma on follow-up. These 15 cases of cervical stratified mucin-producing lesions show a combination of intraepithelial and invasive growth patterns. Given that SMILE is well rooted as a distinct intraepithelial lesion, we propose "invasive stratified mucin-producing carcinoma" to describe its corresponding form of invasive carcinoma.

Cytologic findings in stratified mucin-producing intraepithelial lesion of the cervix: A report of 34 cases.

Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon variant of in situ carcinoma of the cervix. This study aimed to identify the cytologic features of SMILE since these have not been well documented previously. The study group comprised 34 consecutive cases of SMILE encountered at a single institution in which a corresponding Papanicolaou smear, taken up to 12 months before histologic diagnosis, was available for review. The presence of associated cervical neoplastic lesions including cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive carcinoma was recorded. The linear extent and distribution of the SMILEs was also noted. Most Pap smears had been reported to show possible or definite high-grade CIN although 3 cases reported the presence of a high-grade glandular abnormality. No case had a prospective cytologic diagnosis of SMILE. Histology revealed concurrent CIN and/or AIS in all cases, and 1 specimen (3%) showed invasive adenocarcinoma. Following smear review, 23 of the 31 cases that included endocervical material showed recurrent cytologic features that appeared consistent with SMILE. These included three dimensional cell clusters with nuclear stratification and crowding, mild nuclear atypia, cytoplasmic vacuoles, mitotic figures, and apoptosis. SMILE is almost always associated with additional HPV-related neoplastic lesions although only one patient (3%) had invasive carcinoma, a lower rate than recorded in other studies. Consistent cytologic features associated with SMILE were identified but these were relatively subtle. However, increased awareness of these features may permit prospective diagnosis and this could influence patient management.

Stratified mucin-producing intraepithelial lesion (SMILE): report of a case series with associated pathological findings.

Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon premalignant cervical lesion showing morphological overlap with cervical intraepithelial neoplasia (CIN) and adenocarcinoma insitu (AIS)/cervical glandular intraepithelial neoplasia. Given the limited literature on SMILE, we aimed to document its frequency and assess the associated pathology in a large series of cases. Over a 6-year period, we documented all cases of SMILE and the associated findings. SMILE was diagnosed in 69 specimens from 60 patients (50 loop excisions and 19 punch biopsy specimens), constituting 0.6% of cervical specimens. Overall, SMILE coexisted with high-grade CIN in 93% of cases, AIS in 42%, and a carcinoma in 10%. When SMILE was diagnosed on a cervical punch biopsy, there was high-grade CIN in the follow-up loop in most cases. SMILE was consistently diffusely p16-positive and IMP3-negative. Given the morphological overlap and significant association with high-grade CIN and AIS, we believe that SMILE is best regarded as a form of high-grade reserve cell dysplasia, probably arising from reserve or stem cells with the capacity for multidirectional differentiation. We recommend that management of SMILE should be as for AIS.