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Invasive Stratified Mucin-producing Carcinoma (iSMILE) of the Cervix – A Study in

Morphology, Immunohistochemistry and Human Papillomavirus Status

Kay J. Park, MDMemorial Sloan Kettering Cancer CenterNew York (formerly New Amsterdam), NY

USA

INTRODUCTION

tratified ucin-producing ntraepithelial sion

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):1414-1419, October 2000

•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?

Cytoplasmic clearing Discrete vacuoles

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):1414-1419, 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 phenotypicinstability

• 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

2015

Stratified mucin-producing intraepithelial lesion of the cervix: A diagnostic challengeJoerg Schwock,, Marjan Rouzbahman, William R. Geddie.CytoJournal. 2014;11:22.

Diagnostic Cytopathology, Vol. 42, No 9

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. 2010 Feb;148(2):207-9.

Diagnostic Cytopathology, Vol. 44, No 1

American Journal of Surgical Pathology. 40(2):262-269, February 2016.

Invasive SMILE (iSMILE) defined as:Invasive growth with nests or cords of stratified columnar cells that contain intracytoplasmic mucin

Human Pathology (2016) 55, 174–181

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)

iSMILE

• Cell of origin?

• Glandular, Squamous or Both?

• Associated tumors?

• Morphologic variation?

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)

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.)

METHODS

• Morphology of iSMILE and other associated histologic subtypes:– Usual endocervical adenocarcinoma

– Mucinous adenocarcinoma

– Adenosquamous carcinoma

– Pure

– Any other variations

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

RESULTS: iSMILE• Total Adenocarcinomas/Adenosquamous: 409Total iSMILE: 21 (5%)

9 PURE12 ASSOCIATED WITH OTHER SUBTYPES

• 6 USUAL• 3 ADENOSQUAMOUS• 3 MUCINOUS• Other histologic features also noted

RESULTS: Pure iSMILE

Pure iSMILE

iSMILE nested with small lumen formation

iSMILE with Usual Endocervical Adenocarcinoma

iSMILE and Mucinous

iSMILE with extravasated mucin

iSMILE with single cells

iSMILE with signet ring-like cells

iSMILE with and cytoplasmic clearing

iSMILE with micropapillary features

iSMILE with “glassy cell” like features

iSMILE with “glassy cell” like features

iSMILE solid and bizarre nuclei

iSMILE with squamous and squamoid differentiation

RESULTS

IHC

p16

p63 p40 HNF1b

8/12 (67%)

1/11 (9%) 2/7 (29%) 5/12 (42%)

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%

RESULTS: IHC

*2 p53 “null” but on TMA

HPV ISH

RESULTS

12/12 (100%)

3/5 HPV 18

2/5 HPV 16

DISCUSSION

iSMILE is characterized by• Mucin/clear vacuoles throughout thickness

• Nested

• Peripheral palisading

• Neutrophilic infiltrate

• Apoptotic bodies and mitoses

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

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

DISCUSSION

• HPV associated tumor, typically 16 or 18

• p16 less sensitive than HPV ISH (mRNA)

CONCLUSIONInvasive 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???

Thank you

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