Cervix

Premalignant / preinvasive lesions - H&E

LSIL / CIN I



Topic Completed: 11 October 2021

Minor changes: 12 October 2021

Copyright: 2003-2021, PathologyOutlines.com, Inc.

PubMed search: LSIL / CIN I / low grade dysplasia

Hiba Al Dallal, M.B.Ch.B.
Ziyan T. Salih, M.D.
Page views in 2020: 16,131
Page views in 2021 to date: 19,882
Cite this page: Al Dallal H, Salih ZT. LSIL / CIN I. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/cervixLSIL.html. Accessed November 29th, 2021.
Definition / general
  • Usually transient / self limited infection by human papillomavirus (low risk or high risk HPV)
  • This category includes:
    • Flat low grade squamous intraepithelial lesion (LSIL) / cervical intraepithelial neoplasia (CIN) I
    • Exophytic / papillary LSIL (can be immature or mature)
Essential features
  • Low grade squamous lesion caused by low or high risk HPV
  • Koilocytes in the upper layers are characteristic
  • Majority of LSIL regress spontaneously
Terminology
  • Bethesda terminology: low grade squamous intraepithelial lesion (LSIL), use for cytology or cervical biopsies; recommended by LAST project and adopted by the World Health Classification of Female Genital Tumours (IARC 2020) (Arch Pathol Lab Med 2012;136:1266)
  • Alternative terminology (no longer recommended): mild squamous dysplasia, cervical intraepithelial neoplasia I (CIN I)
  • Exophytic forms: immature condyloma, mature condyloma / giant condyloma) (Am J Surg Pathol 2013;37:300, Hum Pathol 1998;29:641)
ICD coding
  • ICD-10: N87.0 - mild cervical dysplasia
Epidemiology
Sites
  • HPV associated LSIL can involve:
    • Cervix
    • Vagina
    • Vulva
    • Anus
    • Penis
    • Scrotum
Pathophysiology
  • LSIL is a heterogenous group caused by
    • Low risk HPV: 6, 11, 42 and 44
    • High risk HPV: 16, 18, 31, 33, 35, 45, 52 and 58
  • HPV is a member of the papovavirus family and consists of a virion containing double stranded, circular DNA surrounded by a protein capsid
    • HPV has 6 E (early) genes (E1, E2, E4, E5, E6, E7) and 2 L (late) genes
    • Called E and L genes depending on when they are expressed during the cycle
    • HPV needs a human host cell to replicate
    • HPV infects squamous cells (a population of reserve / metaplastic cells in the transformation zone of the cervix) (Proc Natl Acad Sci U S A 2012;109:10516)
    • HPV infection begins in the basal layers of the epithelium with expression of the E genes
    • E4 protein of HPV interact with filaggrin (a cytokeratin binding protein), which leads to loss of specific cytokeratin from the cell and collapse of matrix
    • As the cells mature and move toward the surface, L1 and L2 genes are expressed, which are necessary for the viral capsid proteins' transcription
    • In LSIL, the HPV DNA does not integrate into the host DNA and remains in free episomal form; this allows for replication of the virus
    • Koilocytes are filled with complete virions, ready to be discharged
Etiology
Clinical features
  • Asymptomatic
  • Found incidentally on Pap smear screening, cervical biopsy or hysterectomy
Diagnosis
  • Pap smear (cervical cytology screening)
  • Cervical biopsy
Prognostic factors
Treatment
  • Women 30 years of age and older
    • Pap+ and no HPV test or HPV+ → colposcopy
    • Pap+ and HPV- → repeat Pap or cotesting in 1 year → if Pap+ or HPV+ → colposcopy; if both negative, repeat cotesting in 3 years
  • Women aged 21 - 24 years
    • Colposcopy is not recommended; follow up in 1 year
  • Pregnant women
    • Deferring colposcopy until 6 weeks postpartum is acceptable
  • Postmenopausal women
    • HPV testing, repeat cytologic testing at 6 months and 12 months or colposcopy
  • Types of available vaccines
    • HPV bivalent vaccine (Cervarix) will only protect against HPV 16 and 18
    • HPV quadrivalent vaccine (Gardasil) will protect against HPV types 6, 11, 16 and 18
    • HPV 9 valent vaccine, recombinant (Gardasil 9) can protect against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58
  • Reference: Obstet Gynecol 2013;121:829, National Comprehensive Cancer Network: NCCN Guidelines [Accessed 2 June 2021]
Clinical images

Images hosted on other servers:
Colposcopy - acetowhite lesion

Colposcopy - acetowhite lesion

Gross description
  • Flat lesions usually do not produce a grossly identifiable lesion
  • Appears white after application of 3% acetic acid (acetowhite) on colposcopy examination
  • Exophytic lesions can occasionally be seen grossly as small and friable frond-like lesions
Microscopic (histologic) description
  • Flat LSIL
    • Preserved maturation
    • Basal layer preserves polarity while intermediate to superficial cells lose polarity
    • Nuclei in the superficial layer are large, hyperchromatic and irregular with perinuclear halos (koilocytosis / koilocytotic atypia)
    • May show mitotic activity
  • Exophytic LSIL
    • Mature: papillomatosis with preserved maturation and koilocytic atypia
    • Immature: slender papillae with metaplastic immature squamous epithelium and mild koilocytic atypia
    References: Nucci: Gynecologic Pathology, 2nd Edition, 2020, Crum: Diagnostic Gynecologic and Obstetric Pathology, 3rd Edition, 2017
Microscopic (histologic) images

Contributed by Ziyan T. Salih, M.D.
LSIL / koilocytic atypia

LSIL / koilocytic atypia

Koilocytic atypia

Koilocytic atypia

Cervical biopsy (LSIL) Cervical biopsy (LSIL)

Cervical biopsy (LSIL)

Virtual slides

Images hosted on other servers:
Cervical condyloma

Cervical condyloma

LSIL on H&E

LSIL

Spectrum of normal to LSIL to HSIL

Spectrum of normal to LSIL to HSIL

Cytology description
  • Presence of koilocytes: intermediate squamous cell with enlarged hyperchromatic nuclei (1 or multiple nuclei) surrounded by perinuclear halo
  • Nuclear features:
    • Nuclear enlargement comparted to intermediate squamous cell (increased N/C ratio)
    • Dense hyperchromatic chromatin
    • Irregular nuclear membranes
    • Perinuclear clear halo with a well defined, thick cytoplasmic rim
  • See LSIL / CIN I cytology
Cytology images

Contributed by Ziyan T. Salih, M.D.
Koilocytosis (LSIL) Koilocytosis (LSIL)

Koilocytosis (LSIL)

Negative stains
  • p16 is usually negative or weak and patchy, although lesions caused by high risk HPV will show overexpression (~33% of cases), limiting its use as a biomarker (Int J Surg Pathol 2012;20:146)
Molecular / cytogenetics description
  • Molecular assays available based on RNA ISH include:
    • HPV E6 / E7 mRNA in situ hybridization (ISH) assay covering 18 common high risk types (HR-RISH, aka HR-HPV RNA18 ISH)
    • HR-RISH was also positive in 78% of anogenital low grade squamous intraepithelial lesion, including 81% of CIN1 (Am J Surg Pathol 2017;41:607)
  • Molecular assays based on the detection of HPV DNA include:
    • Nonamplified hybridization assays, such as Southern transfer hybridization (STH), dot blot hybridization (DB) and in situ hybridization (ISH)
    • Signal amplified hybridization assays, such as hybrid capture assays (HC2)
    • Target amplification assays, such as polymerase chain reaction (PCR) and in situ PCR (Int J Biol Markers 2009;24:215)
Videos

Squamous lesions of the cervix and their differential diagnosis
by Carlos Parra-Herran, M.D.

Sample pathology report
  • Cervix, biopsy:
    • Low grade squamous intraepithelial lesion (LSIL) / CIN I (see comment)
Differential diagnosis
  • Inflammatory changes / repair:
    • Nuclei are round, uniform and lack hyperchromasia
  • Squamous metaplasia:
    • Cells with mucin vacuoles, nuclei lack hyperchromasia
  • Radiation and chemotherapy effects:
    • Previous history, low N/C ratio
  • High grade squamous intraepithelial lesion (HSIL):
    • Shows hyperchromatic crowded squamous cells with high N/C ratio, present throughout the epithelium
    • Mitotic figures are seen above the basal layer
    • p16 shows block type staining in most HSILs; however, about 33% of LSILs also show p16 overexpression; therefore, p16 helps only if it is negative or patchy (not overexpressed), as it excludes HSIL and would be supportive of LSIL in the right diagnostic context
Board review style question #1

A cervical cone biopsy from a 37 year old woman is shown above. The majority of these lesions will

  1. Persist
  2. Progress to higher grade
  3. Progress to invasive cancer
  4. Regress
Board review style answer #1
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Image 01 Image 02