Cervix - cytology
Premalignant / preinvasive lesions
LSIL / CIN I / low grade dysplasia

Author: Erika M. Baardsen, D.O. (see Authors page)
Editor: Marilin Rosa, M.D.
Editorial Board Member Review: Carlos Parra-Herran, M.D.

Revised: 23 October 2017, last major update September 2017

Copyright: (c) 2002-2017, PathologyOutlines.com, Inc.

PubMed search: LSIL[title]

Cite this page: Baardsen, E. LSIL / CIN I / low grade dysplasia. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/cervixcytologyLSIL.html. Accessed December 13th, 2017.
Definition / general
  • Low grade squamous intraepithelial lesion (LSIL) is part of the spectrum of squamous cell changes associated with HPV infection
  • Also known in former literature as mild squamous dysplasia and cervical intraepithelial neoplasia I (CIN I)
  • LSIL is identified in approximately 2 - 3% of all Pap smears
Essential features
  • Approximately half of all LSIL cases regress spontaneously without intervention
  • High risk HPV is detected in approximately 77% of LSIL cases
  • Most common high risk HPV types are 16, 18, 31 and 33
  • Key cytomorphologic features:
    • Single, clusters or sheets of cells of intermediate to large size
    • Nuclear enlargement 3 or more times greater than a normal intermediate nucleus
    • Nuclear atypia may include: irregular contours, hyperchromasia and chromatin ranging from coarsely granular to smudgy
    • Koilocytosis
    • Binucleation and multinucleation are common
    • Nucleoli are absent
    • Increased keratinization with dense orangeophilic cytoplasm may be seen
Pathophysiology
  • HPV genome consists of about 8,000 base pairs of circular double stranded DNA that codes for 8 genes, which are classified as "early" (E) or "late" (L)
  • HPV infection is established in the basal layer of epithelium with a strong predilection for the transformation zone; as epithelium matures, gene amplification and viral assembly occur, with expression of L1 (major viral capsid protein - major component of HPV vaccines) and L2
  • E6 and E7 gene products are the most significant in malignant transformation; binding of E6 to p53 results in blocking of apoptosis and binding of E7 to retinoblastoma tumor suppressor protein leads to uninhibited cellular proliferation
Etiology
  • HPV 16 is the prototype of high risk viruses and most commonly detected in cervical cancers
  • High risk HPV types include: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
Diagnosis
  • Cervical carcinoma screening should begin at 21 years of age, independent of sexual history or behavioral risk factors
  • Due to the high prevalence of otherwise inconsequential HPV infection in young women, HPV testing alone is not a useful triage strategy in this population
  • Women between the ages of 21 and 29 should receive cervical cytology screening alone every three years
  • Women between 30 and 65 years of age should be co-tested with cytology and HPV testing every five years; alternatively, they can be tested with cytology alone every three years (Obstet Gynecol Clin North Am 2013;40:211, Ann Intern Med 2012;156:880)
  • Screening should be discontinued for women after the age of 65 if they have had adequate negative screening
Prognostic factors
  • ~ 47% of LSIL cases regress
  • ~ 21% progress to HSIL
  • Less than 1% progress to invasive squamous cell carcinoma
  • Women with HPV 16 are at particular risk for HSIL / CIN or invasive carcinoma
Management
  • Current ASCCP management guidelines recommend (ASCCP: Guidelines):
    • Women less than 25 years of age with LSIL: follow up with repeat Pap in 12 months
    • Women 25 years or older with LSIL and either no HPV test or a positive HPV test: colposcopy is recommended
    • Women 25 years and older with LSIL that are HPV negative: repeat co-testing at 1 year is preferred but colposcopy is acceptable
    • Pregnant women with LSIL: colposcopy is preferable but deferring colposcopy until 6 weeks postpartum is acceptable
    • Postmenopausal women with LSIL and no HPV test: HPV testing, repeat cytologic testing at 6 months and 12 months and colposcopy
Cytology description
  • Single, clusters or sheets of cells of increased sized and abundant mature, well defined cytoplasm
  • Nuclear enlargement 3 or more times greater than a normal intermediate nucleus
  • Koilocytosis or perinuclear cavitation consists of broad, well demarcated clear perinuclear zone outlined by a peripheral rim of densely stained (condensation) cytoplasm
  • Nuclei may be hyperchromatic (more evident on conventional preps) with uniformly distributed chromatin that ranges from coarsely granular to smudgy
  • Nuclear contours range from smooth to markedly irregular
  • Binucleation and multinucleation are common
  • Nucleoli are absent
  • Increased keratinization with dense orangeophilia cytoplasm may be seen
  • Koilocytosis or dense orangeophilia must also show nuclear abnormalities to qualify as LSIL
Cytology images

Images hosted on PathOut server:

Images contributed by Marilin Rosa, M.D., University of Florida:

LSIL



Images hosted on other servers:

Various images

Molecular / cytogenetics description
  • HPV testing can be used as triage of abnormal cytology results, as co-testing or as a primary screening test (Gynecol Oncol 2015;136:178)
  • In 2014, the FDA approved HPV DNA test (cobas® HPV test, Roche Molecular Systems, Inc.) as a first line primary screening test for use alone for women age 25 and older; this test detects each of HPV types 16 and 18 and gives pooled results for 12 additional high risk HPV types
  • Other FDA approved methods include:
    • Digene® HPV test using Hybrid Capture® 2 (HC2) technology (Qiagen, Germany)
    • Cervista® HPV HR assay (Hologic, Inc., Marlborough, MA, USA)
    • APTIMA® HPV assay (Gen-Probe, Hologic, Inc.)
Differential diagnosis
  • Atypical squamous cells of undetermined significance (ASC):
    • Lesions with borderline nuclear changes that are not diagnostic of definitive LSIL
  • Herpes cytopathic effect:
    • Multinucleated cells showing nuclear molding, margination of chromatin and clear, ground glass nuclei
    • Early herpes effect may lack diagnostic nuclear features but may have nuclear enlargement, hyperchromasia and degenerative chromatin, which can be mistaken for LSIL
    • These cells lack other HPV related cytopathic effects, such as koilocytosis
  • HSIL
  • Keratinized squamous cells:
    • Parakeratosis refers to squamous cells with round to oval, small pyknotic nuclei and low nuclear to cytoplasmic (N/C) ratios
    • Not an HPV related entity by itself but may be found as a background pattern in HPV associated lesions
    • If nuclear abnormalities and low N/C ratios are present, the lesion should be categorized as atypical squamous cells of undetermined significance (ASC) or higher
  • Pseudokoilocytes:
    • Glycogen in squamous cells may resemble koilocytes
    • Halos associated with glycogen often have yellow refractile appearance
    • Nuclear features of LSIL are not present
  • Radiation atypia:
    • Cells have low N/C ratio with large nuclei, similar to that seen in LSIL
    • Cytoplasm is usually two toned and vacuolated, lacking perinuclear clearing and peripheral cytoplasmic condensation seen in typical koilocytes
Board review question #1
A 32 year old pregnant woman undergoes routine Pap screening. Her results reveal low grade squamous intraepithelial lesion (LSIL) with positive HPV test. What is the next best step in the management of this patient?

  1. Colposcopy
  2. Defer colposcopy to 6 weeks postpartum
  3. No additional follow up is necessary
  4. Repeat Pap test in 12 months
  5. Repeat Pap with co-testing in 3 years
Board review answer #1
A. Colposcopy. According to ASCCP management guidelines, pregnant women with positive HPV tests are recommended to undergo colposcopy. Despite colposcopy being the preferred management strategy, deferral of colposcopic examination to 6 weeks postpartum is acceptable (answer B).