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1 Enterprise Interest None

2 Invasive Stratified Mucin-producing Carcinoma (ismile) of the Cervix A Study in Morphology, Immunohistochemistry and Human Papillomavirus Status Kay J. Park, MD Memorial Sloan Kettering Cancer Center New York (formerly New Amsterdam), NY USA

3 INTRODUCTION

4 tratified ucin-producing ntraepithelial sion

5 Stratified Mucin-Producing Intraepithelial Lesions of the Cervix: Adenosquamous or Columnar Cell Neoplasia? Park, Jeong-Ja; Sun, Deqin; Quade, Bradley; Flynn, Cythia; Sheets, Ellen; Yang, Annie; McKeon, Frank; Crum, Christopher AJSP 24(10): , October 2000 Cytoplasmic clearing Discrete vacuoles Immature intraepithelial lesion with stratified cells similar to CIN Conspicuous mucin or cytoplasmic clearing separating cells throughout Absence of classic gland formation (AIS) Mucicarmine highlights mucin throughout Resembles SIL when mucin poor Adenosquamous lesion or columnar cell variant?

6 Stratified Mucin-Producing Intraepithelial Lesions of the Cervix: Adenosquamous or Columnar Cell Neoplasia? Park, Jeong-Ja; Sun, Deqin; Quade, Bradley; Flynn, Cythia; Sheets, Ellen; Yang, Annie; McKeon, Frank; Crum, Christopher AJSP 24(10): , October 2000 Associated lesions with SMILE (n=18) CIN2-3, AIS, adenocarcinoma, adenosquamous carcinoma, squamous carcinoma 9/18 (50%) associated with invasive carcinoma Adenocarcinoma (n=4) Adenosquamous carcinoma (n=5) SCC (n=1) Marker of phenotypic instability

7 Coexistence with other findings: 7 cases of SMILE associated with invasive ca 6 SCC, 1 Adeno AIS present in 42% CIN present in 93% IHC IMP3 negative (closer to CIN than AIS immunophenotypically) p16 diffuse strong Reserve cell dysplasia preferred, management like AIS

8 Diagnostic Cytopathology, Vol. 42, No 9 Diagnostic Cytopathology, Vol. 44, No Follow-up of patients with SMILE (stratified mucin producing intraepithelial lesion) on the cervix--a dilemma. Gupta S, Parsons P, Saha A, Wight C. Eur J Obstet Gynecol Reprod Biol Feb;148(2): Stratified mucin-producing intraepithelial lesion of the cervix: A diagnostic challenge Joerg Schwock,, Marjan Rouzbahman, William R. Geddie. CytoJournal. 2014;11:22.

9 American Journal of Surgical Pathology. 40(2): , February 2016.

10 Human Pathology (2016) 55, Invasive SMILE (ismile) defined as: Invasive growth with nests or cords of stratified columnar cells that contain intracytoplasmic mucin 9 invasive carcinomas associated with SMILE 5 Adenocarcinoma (E) (3 ismile, 2 Usu, 1 Villog) 2 Adenosquamous carcinoma 1 Adenoca and separate SCC 1 Large cell neuroendocrine carcinoma (F)

11 ismile Cell of origin? Glandular, Squamous or Both? Associated tumors? Morphologic variation?

12 OBJECTIVE To determine the frequency of ismile in a cohort of adenoca and adenosquamous ca To describe the morphologic variation of ismile and any other associated histotypes To determine the immunohistochemical profile of ismile To determine HPV status and interrogate specific HPV subtypes (16, 18, 45)

13 METHODS Part of a larger study of endocervical adenocarcinomas All cases called adenocarcinoma or adenosquamous carcinoma were reviewed Categorized by histologic subtype Adenocarcinoma Adenosquamous carcinoma Glassy cell carcinoma Adenocarcinoma with squamous metaplasia ismile (used definition of Lastra et al.)

14 METHODS Morphology of ismile and other associated histologic subtypes: Usual endocervical adenocarcinoma Mucinous adenocarcinoma Adenosquamous carcinoma Pure Any other variations

15 METHODS Tissue microarray (TMA) constructed Immunohistochemistry and HPV detection performed RNAscope E6/E7 mrna Detects transcriptionally active HPV 16,18,26,31,33,35,39,45,51, 52,53,56,58,59,66,68,73,82 Type specific HPV 16, 18 and 45 also performed

16 RESULTS: ismile Total Adenocarcinomas/Adenosquamous: 409 Total ismile: 21 (5%) 9 PURE 12 ASSOCIATED WITH OTHER SUBTYPES 6 USUAL 3 ADENOSQUAMOUS 3 MUCINOUS Other histologic features also noted

17 RESULTS: Pure ismile

18 Pure ismile

19 ismile nested with small lumen formation

20 ismile with Usual Endocervical Adenocarcinoma

21 ismile and Mucinous

22 ismile with extravasated mucin

23 ismile with single cells

24 ismile with signet ring-like cells

25 ismile with and cytoplasmic clearing

26 ismile with micropapillary features

27 ismile with glassy cell like features

28 ismile with glassy cell like features

29 ismile solid and bizarre nuclei

30 ismile with squamous and squamoid differentiation

31 RESULTS IHC

32 p16 8/12 (67%) p63 p40 HNF1b 1/11 (9%) 2/7 (29%) 5/12 (42%)

33 RESULTS: IHC POSITIVE NEGATIVE P16 (8/12) 67% HIK1083 PAX8 (2/7) 29% SATB2 P40 (2/7) 29% CDX2 P63 (1/11) 9% AR PR (3/12) 25% *p53 (2/11) 18% CA-IX (4/7) 57% MUC6 (4/7) 57% HNF1beta (5/12) 42% GATA 3 (1/7) 14% Vimentin (1/12) 8% Her2 (1/12-2+) 8% *2 p53 null but on TMA

34 RESULTS HPV ISH 12/12 (100%) 3/5 HPV 18 2/5 HPV 16

35 DISCUSSION ismile is characterized by Mucin/clear vacuoles throughout thickness Nested Peripheral palisading Neutrophilic infiltrate Apoptotic bodies and mitoses

36 DISCUSSION Question of adenocarcinoma vs adenosquamous P40 and p63 often positive, patchy pattern, typically in peripheral cells PAX8 less frequently positive The frequent expression of p63/p40 and lack of PAX8 in ismile suggests that it is likely of reserve cell origin TMA study has limitations

37 DISCUSSION The presence of mucin suggests it is differentiating toward glandular epithelium The frequent association with other subtypes suggests a phenotypic fluidity Usual endocervical adenocarcinoma Squamous diff (keratin or intercellular bridges) Glassy cell-like Signet ring-like Micropapillary Clear cytoplasm

38 DISCUSSION HPV associated tumor, typically 16 or 18 p16 less sensitive than HPV ISH (mrna)

39 CONCLUSION Invasive Stratified Mucin-producing Carcinoma HPV associated (16, 18) Morphologically distinct but with Phenotypic fluidity can be pure or mixed and often thought to be adenosquamous carcinoma Likely of reserve cell origin and retains pluripotential ability True Adenosquamous???

40 Thank you

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44 No pictures but suggests at least some of their cases were probably invasive SMILE

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