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Invasive stratified mucin producing carcinoma


Andreas Kontosis, M.D.
Julieta E. Barroeta, M.D.

Last author update: 29 July 2024
Last staff update: 29 July 2024

Copyright: 2022-2024, PathologyOutlines.com, Inc.

PubMed Search: Invasive stratified mucin producing carcinoma

Andreas Kontosis, M.D.
Julieta E. Barroeta, M.D.
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Kontosis A, Barroeta JE. Invasive stratified mucin producing carcinoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cervixinvasivestratifiedmucincarc.html. Accessed December 24th, 2024.
Definition / general
  • Variant of the mucinous type of human papillomavirus (HPV) associated adenocarcinoma of the cervix
Essential features
  • Second most common type of HPV associated cervical adenocarcinoma
  • Considered the invasive counterpart of stratified mucin producing intraepithelial lesion (SMILE) and is associated with high risk HPV infection (most commonly HPV 18 followed by HPV 16)
  • Typical histologic features include solid invasive nests of stratified mucinous cells often exhibiting peripheral nuclear palisading, apoptotic bodies, mitoses and an associated neutrophilic infiltrate
  • May demonstrate morphologic variability including areas of usual type endocervical adenocarcinoma; it can be mixed with other types of carcinomas
  • Both pure and mixed tumors show increased rates of local recurrence and lymph node metastasis and a worse prognosis compared to usual type HPV associated adenocarcinoma
Terminology
  • Stratified mucin producing carcinoma
  • i-SMILE and iSMILE
  • Invasive stratified mucinous carcinoma (iSMC)
  • Invasive stratified mucin producing carcinoma (ISMC)
  • HPV associated endocervical adenocarcinoma, invasive stratified mucin producing type
ICD coding
  • ICD-O
    • 8482/3 - mucinous adenocarcinoma, endocervical type
    • 8483/3 - HPV associated adenocarcinoma
    • 8481/3 - mucin producing adenocarcinoma
  • ICD-11: 2C77.1 & XH1S75 - adenocarcinoma of cervix uteri & mucinous adenocarcinoma
Epidemiology
Sites
  • Arises at the transformation zone of the cervix
Pathophysiology
  • Considered the invasive counterpart of stratified mucin producing intraepithelial lesion of the cervix (Am J Surg Pathol 2016;40:262)
    • Believed to arise from cervical reserve cells after persistent infection by high risk HPV serotypes (Am J Surg Pathol 2020;44:873)
      • Basally located stem cells under columnar epithelium near the squamocolumnar junction (transformation zone); can be differentiated into both squamous and glandular cells as well as express squamous and glandular lineage specific markers, respectively (Cancer Med 2020;9:6330)
      • Supporting evidence
        • Expression of p63 and CK5/6 in the peripheral palisading cells in ISMC
        • Distinct stemness and epithelial - mesenchymal transition (EMT) prone features of ISMC (Mod Pathol 2021;34:1738)
        • Ability to present variable architectural and cytologic patterns (Am J Surg Pathol 2020;44:873)
    • HPV targets cells capable of both squamous and columnar differentiation (Am J Surg Pathol 2000;24:1414)
Etiology
  • Associated with high risk HPV infection (HPV 18 is the most common subtype, followed by HPV 16 and rarer subtypes [e.g., HPV 52, 45 and 59]) (Cancer Epidemiol 2023;86:102442)
Clinical features
Diagnosis
  • See HPV associated adenocarcinoma
  • Abnormal Pap smear or high risk HPV testing results may lead, depending on risk assessment, to colposcopy and biopsy (J Low Genit Tract Dis 2020;24:102)
  • Biopsy is the gold standard for the definite diagnosis
  • Diagnostic criteria (WHO 5th edition)
    • Essential
      • Stromal invasion, either destructive or nondestructive
      • Solid invasive nests of stratified mucinous cells
      • Absence of endometrioid confirmatory features such as squamous metaplasia and endometriosis
    • Desirable
      • p16 overexpression
      • HPV detection
      • Negative ER, PR and usually vimentin
      • Wild type p53
Prognostic factors
  • More aggressive clinical course as compared to usual type endocervical adenocarcinoma (Histopathology 2024;84:315)
    • More likely to be higher grade, have larger size, advanced FIGO stage and lymph node metastasis
    • Worse overall survival and shorter tumor recurrence
  • 5 year overall survival (OS) (Am J Surg Pathol 2020;44:1374)
    • 88.9% for FIGO stage I
    • 30% for FIGO stages II - IV
  • 5 year recurrence free survival (RFS)
    • 73.9% for FIGO stage I
    • 38.1% for FIGO stages II - IV
  • Prognostic factors (affecting overall survival and recurrence free survival)
    • FIGO stage
    • Tumor size
    • Lymph node metastasis
    • Local recurrence
    • Type of surgical treatment (if lymph node dissection is included or not) appears to affect RFS but not OS (Am J Surg Pathol 2020;44:1374)
  • Pure iSMCs when compared with mixed iSMCs are more likely to have
Case reports
Treatment
  • No consensus for specific treatment of ISMC; treat like other cervical adenocarcinomas (Arch Gynecol Obstet 2022;306:1703)
  • It is suggested that ISMC should be treated with radical surgery and lymph node dissection, regardless of the size of tumor and proportion of iSMC component in mixed tumors, since extent of surgery (inclusion or not of lymph node dissection) can affect prognosis (indicated by RFS data) (Am J Surg Pathol 2020;44:1374)
    • Potential role of PD-1 / PDL1 immunotherapy, since ISMC (70 - 100%) shows overexpression of PDL1, with combined positive score (CPS): 30 - 100 and 1 - 92 in 2 studies (Cancer Genomics Proteomics 2021;18:685)
  • Amplification of ERBB2 or c-erB2 overexpression observed in few cases
Gross description
Microscopic (histologic) description
  • Classic ISMC features
    • Solid infiltrative nests of stratified mucinous cells
      • Mucin can be variable, ranging from mucin poor to mucin rich tumors
    • Distinct nuclear palisading at the periphery of the nests
    • Bland (usually mild to moderate pleomorphic), oval or round nuclei with indistinct nucleoli
    • Easily identified mitotic figures and apoptotic bodies
    • Intratumoral and peritumoral neutrophilic infiltrates
    • May have adjacent foci of stratified mucin producing intraepithelial lesion (Am J Surg Pathol 2016;40:262)
  • Can present as pure ISMC (ISMC ≥ 90% of tumor) or mixed with other carcinomas (mixed ISMC) (ISMC ≥ 10% and < 90%) (Histopathology 2024;84:315)
    • Usual type adenocarcinoma (most common) followed by adenosquamous, mucinous adenocarcinoma not otherwise specified and rarely neuroendocrine carcinoma (NEC) (Am J Surg Pathol 2020;44:1374)
  • Other rare morphologic features have been described
    • Architecture patterns: insular, trabecular, glandular, solid, papillary, micropapillary and single cells
    • Cytoplasm can have intracellular mucin and also be glassy-like, clear, delicately eosinophilic, dense eosinophilic (giving a squamoid appearance), histiocytoid or with signet ring features
    • Bizarre nuclear atypia, extravasated pools of mucin and hyaline-like globules have been reported (Am J Surg Pathol 2020;44:873)
  • Invasion may be expansile or destructive
  • Overlying intraepithelial lesions can be identified if not overgrown by the tumor
    • Most commonly stratified mucin producing intraepithelial lesion but also HSIL and adenocarcinoma in situ (AIS) or a combination (Am J Surg Pathol 2020;44:873)
Microscopic (histologic) images

Contributed by Julieta E. Barroeta, M.D., Andreas Kontosis, M.D. and Ricardo R. Lastra, M.D.
Infiltrative nests   Infiltrative nests

Infiltrative nests

Intratumoral and peritumoral inflammation

Intratumoral and peritumoral inflammation

Metastatic ISMC

Metastatic ISMC

SMILE and AIS

SMILE and AIS


Mucicarmine

Mucicarmine

p16 IHC

p16 IHC

PAX8 IHC

PAX8 IHC

p40 IHC

p40 IHC

ER IHC

ER IHC

Positive stains
Negative stains
Electron microscopy description
  • Stratified structure
  • Cells with elongated and irregularly shaped nuclei
  • Abundant mitochondria and rough endoplasmic reticulum in the cytoplasm
  • Some cells with intracytoplasmic mucous vacuoles
  • Primitive cell junctions present but without tonofilaments (Hum Pathol 2016:55:174)
Molecular / cytogenetics description
  • HPV ISH with nuclear positivity; HPV 18 E7 PCR is the most common product (Hum Pathol 2016:55:174)
  • Low mutational burden (average mutation rate is 5.9 mutations per lesion) and microsatellite stable status (J Transl Med 2022;20:187, Mod Pathol 2021;34:1738)
  • Different results from a limited number of studies
    • Whole exome analysis in 8 cases showed (J Transl Med 2022;20:187)
      • MUC4 mutations in pure ISMCs
      • DMD (encodes dystrophin protein) and DMKN mutations in mixed ISMCs
      • Gene alterations in epithelial - mesenchymal transition (EMT) related, Notch and Wnt signaling pathways consistent with EMT capabilities of ISMCs
    • Targeted sequence analysis of 10 cases showed (Mod Pathol 2021;34:1738)
      • TWIST1, AKT2, GNAQ, PTEN and SF3B1 mutations only in pure ISMCs
      • STK11, MET, ERB2 and KMT2D EMT related mutations, in both pure and mixed ISMCs
      • STK11, MET, FANCA and PALB2 mutations preferentially expressed in ISMCs compared to endocervical adenocarcinomas and squamous cell carcinoma (SCC)
    • Targeted sequence of 8 cases showed (Cancer Genomics Proteomics 2021;18:685)
      • ERBB3, KRAS, ERBB2, PIK3CA and GNAS mutations
      • ERBB2 amplification in 1 case
Sample pathology report
  • Uterus, cervix, bilateral fallopian tubes and ovaries, radical hysterectomy with bilateral salpingo-ophorectomy and (pelvic) lymph node dissection:
    • HPV associated endocervical adenocarcinoma, pure / mixed (invasive) stratified mucin producing carcinoma (percentage%) and usual type adenocarcinoma (percentage%) (see comment)
    • Size: __ cm in greatest dimension
    • Silva A / B / C pattern of invasion
    • Depth of invasion: __ mm (superficial third, middle third or deep third of cervical wall)
    • Lymphovascular invasion present / absent
    • Associated in situ lesions (AIS, SMILE or HSIL) present
    • Surgical resection margins negative for in situ and invasive carcinoma (see synoptic report)
    • TNM and FIGO staging
    • Comment: Invasive stratified mucin producing carcinoma is a variant of mucinous type of HPV associated adenocarcinomas of the cervix and it has been associated with a higher risk of lymph node metastases, higher risk of recurrence and a worse prognosis.
Differential diagnosis
Board review style question #1


Which of the following statements is true regarding the cervical carcinoma shown above?

  1. HPV 16 is the most common identifiable HPV subtype
  2. It is considered the invasive counterpart of stratified mucin producing intraepithelial lesion (SMILE) of the cervix
  3. It is the most common type of HPV associated cervical adenocarcinoma
  4. It rarely shows lymph node metastasis
Board review style answer #1
B. It is considered the invasive counterpart of stratified mucin producing intraepithelial lesion (SMILE) of the cervix. As the name implies, invasive stratified mucin producing carcinoma (ISMC) shows morphologic similarities with the stratified mucin producing intraepithelial lesions of the cervix, which can be identified in the nearby mucosa and are considered precursor lesions. Answer A is incorrect because ISMC is most commonly associated with HPV subtype 18. Answer C is incorrect because usual type endocervical adenocarcinoma (UEA) is the most common HPV associated cervical adenocarcinoma. Answer D is incorrect because it frequently metastasizes to the lymph node and ~33% of patients can present with lymph node metastasis.

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Reference: Invasive stratified mucin producing carcinoma
Board review style question #2
Which immunohistochemical profile would most likely be seen in an invasive stratified mucin producing carcinoma (ISMC) of the cervix?

  1. PAX8- / p16- / p40- / CK7-
  2. PAX8+ / p16- / p40- / CK7+
  3. PAX8- / p16+ / p40+ / CK7+
  4. PAX8- / p16+ / p40- / CK7+
Board review style answer #2
D. PAX8- / p16+ / p40- / CK7+. Invasive stratified mucin producing carcinoma of the cervix (ISMC) shows positivity for CK7 and p16 (block-like) and is negative for PAX8 (can be focally positive). p40 IHC can sometimes highlight the palisading nuclei at the periphery of the neoplastic nests but is negative for the other neoplastic cells. Answer A is incorrect because ISMC is an HPV associated adenocarcinoma and thus stains positive for p16. CK7 is also positive in ISMC. Answer B is incorrect because this immunohistochemical profile can be seen in endometrial endometrioid adenocarcinoma, among other diagnoses. Answer C is incorrect because this immunohistochemical profile is consistent with HPV associated cervical squamous cell carcinoma.

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Reference: Invasive stratified mucin producing carcinoma
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