Histopathology

From Cancer Guidelines Wiki



Background

The histopathological classification of HPV-associated disease of the anogenital tract prior to 2012 was complex. Terminology changed for different sites and variable terms such as condyloma, dysplasia, intraepithelial neoplasia and carcinoma in-situ were employed. This was partly due to development of a number of different interest groups including pathologists, dermatologists and gynaecologists using their own version of terminology for similar lesions.

LASTLower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions

To address this problem and to improve communication between the specialties, the Lower Anogenital Squamous Terminology (LASTLower Anogenital Squamous Terminology) Standardization Project for HPV-Associated Lesions was convened, including five major working groups. The findings were first published in June 2012,[1] with two further publications within the following 12 months in order to reach a broad audience.[2][3]

The LASTLower Anogenital Squamous Terminology Standardization Project working groups recognised a number of general principles:[1]

  • HPV-related squamous disease reflects a unified epithelial biology.
  • Each cytological or histological sample provides only a statistical representation of the patient’s true biology; the more samples or data points available, the more accurate the assessment of the patient’s true biology.
  • The true biology represents the risk for cancer at the current time, and the risk for cancer over time.
  • Diagnostic variation can be improved by:
  • aligning the number of diagnostic terms with the number of biologically relevant categories
  • the use of biological markers.

The findings of the LASTLower Anogenital Squamous Terminology project have been widely accepted and adopted by members of the Royal College of Pathologists of Australasia (RCPARoyal College of Pathologists of Australasia) and the World Health Organization (WHO)[4], and have been referenced in the first edition (2013) of the RCPARoyal College of Pathologists of Australasia protocol for structured reporting of cervical carcinoma[5].

Back to top

Two tiered nomenclature

A two-tiered nomenclature system has been accepted for non-invasive HPV associated squamous proliferations of cervix and lower anogenital tract. The two groups are LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category. and HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology).. These two groups may be further characterised by the applicable intraepithelial neoplasia or –IN subcategory. The nomenclature addresses pre-invasive mucosal lesions and early invasive mucosal lesions.

Low-grade squamous intraepithelial lesion (LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category.)

LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category. is the morphologic expression of acute HPV infection and is characterised by cells with increased nuclear to cytoplasmic ratios and irregular nuclear membranes. Mitoses are limited to the lowermost third of the epithelium and maturation begins in the middle third. Multi-nucleation and perinuclear halos, characteristic of HPV effect, may be seen. LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category. encompasses changes previously called ‘HPV effect’ and CIN1mild dysplasia (pre-AMBSAustralian Modified Bethesda System 2004). The LASTLower Anogenital Squamous Terminology terminology does not support the distinction between these two categories because of poor inter-observer agreement, lack of clinical significance and the common underpinning biology. In cases with LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category. morphology, p16 staining should not be performed.

High-grade squamous intraepithelial lesion (HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology).)

HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). is the morphologic expression of persistent HPV infection that has the potential to progress to invasive carcinoma. It is characterised by mitoses seen at any level of the epithelium, little to no cytoplasmic differentiation in the middle third and upper third, increased nuclear size, and irregular nuclear membranes. Where the pathologist is considering a diagnosis of CIN2, p16 staining should be performed.

The result for p16 is reported as positive if there is strong and diffuse block staining for p16. In squamous epithelia, this is defined as continuous strong nuclear, or nuclear plus cytoplasmic, staining of the basal cell layer with extension upward involving at least one-third of the epithelial thickness.[2] The LASTLower Anogenital Squamous Terminology Standardization Project group notes that this height restriction is somewhat arbitrary but adds specificity, and that full-thickness staining or extension into the upper third or upper half is specifically not required to call a specimen positive.[2]

When the p16 stain is negative the lesion is either LSILLow-grade squamous intraepithelial lesionThe low-grade squamous intraepithelial lesion (LSIL) category is the morphological correlate of productive viral infection. It is to be used when the scientist/pathologist observes changes that would have been described as ‘HPV effect’ or ‘CIN 1’ in the previous Australian terminology and represents part of the previous ‘low-grade squamous epithelial abnormality’ category. or a mimic of HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). and, accordingly, should not be diagnosed as HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology)..

HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). encompasses lesions previously called ‘CIN2’ and ‘CIN3’. The following subcategories should continue to be used:

  • HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN2) – used when p16 positive
  • HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology). (CIN3).

This practice will enable continued measurement of the prevalence of CIN3 in Australian women during and after transition to the renewed NCSPNational Cervical Screening ProgramA joint program of the Australian, state and territory governments. It aims to reduce morbidity and mortality from cervical cancer, in a cost-effective manner through an organised approach to cervical screening. The program encourages women in the target population to have regular Pap smears..

Back to top

Superficially invasive squamous cell carcinoma (SISCCASuperficially invasive squamous cell carcinoma (previously termed 'Micro-invasive carcinoma'))

The term ‘microinvasive carcinoma’ is no longer recommended, and the term ‘superficially invasive squamous cell carcinoma’ (SISCCASuperficially invasive squamous cell carcinoma (previously termed 'Micro-invasive carcinoma')) should be used instead. It is recognised that SISCCASuperficially invasive squamous cell carcinoma (previously termed 'Micro-invasive carcinoma') has a favourable prognosis.

A report including the finding of SISCCASuperficially invasive squamous cell carcinoma (previously termed 'Micro-invasive carcinoma') must include a comment on the presence or otherwise of lymphatic invasion and a comment on the number and size of multifocal carcinomas, once the presence of a single carcinoma is excluded. The International Federation of Gynecology and Obstetrics (FIGOThe International Federation of Gynaecology and Obstetrics) staging should be based on the highest FIGOThe International Federation of Gynaecology and Obstetrics stage of an individual focus, rather than adding multiple foci together.[6]

Squamous cell carcinoma (SCCSquamous cell carcinoma)

Squamous cell carcinoma is an invasive epithelial tumour showing variably differentiated squamous cells.[7] The majority are of large cell keratinizing type, demonstrating sheet-like growth, with surrounding desmoplastic stromal response. Virtually all SCCs are thought to arise from a pre-cancerous intraepithelial lesion (HSILHigh-grade squamous intraepithelial lesionIn the Australian context, HSIL is used to refer to a cytology predictive of a high grade precancerous lesion (AMBS 2004), or histologically confirmed high grade precancerous lesion (HSIL-CIN2 or HSIL-CIN3 as per LAST terminology).).[7]

Biomarkers

The LASTLower Anogenital Squamous Terminology group assessed data on p16, Ki-67 (Mib1), ProEx C, L1, HPV 16/18Only HPV types 16 and or 18 detected using routine HPV screening tests in laboratory. mRNA, telomerase/TERC, and HPV genotyping. It concluded that p16 was the only biomarker for which there was sufficient evidence to recommend its use for distinguishing between types of mucosal pre-cancerous lesions. Staining for p16 is particularly useful for lesions with inflammation or atrophy, lesions affected by diathermy, and thin lesions.

Back to top

Glandular proliferations

Adenocarcinoma in-situ (AISAdenocarcinoma in situ)

‘Adenocarcinoma in situ’ (AISAdenocarcinoma in situ) is the only currently recommended term in Australasia for glandular mucosal pre-invasive lesions.[8] The term ‘glandular dysplasia’ is not currently used in Australia, but has been used historically and is in use in the United Kingdom (where the synonym is ‘low grade cervical glandular intraepithelial neoplasia’).[9]

AISAdenocarcinoma in situ is an intraepithelial lesion containing malignant-appearing glandular epithelium. Nuclei are hyperchromatic and stratified, mitoses are frequently seen towards the apex of the cell, and apoptotic debris may be seen towards the base of the cell. The use of p16 can be very effective in distinguishing AISAdenocarcinoma in situ from mimics including tubular metaplasia following previous surgical treatment.[9]

Invasive adenocarcinoma of cervix

Adenocarcinoma of cervix is an invasive epithelial tumour showing glandular differentiation.[7] There is significant morphological overlap with adenocarcinoma in situ. However, clues to the invasive nature of the lesion include a desmoplastic stromal response, small angulated claw-like glands branching from the areas of AISAdenocarcinoma in situ and complex architectural proliferations such as solid, papillary cribriform and labyrinthine growth patterns.[10] Several subtypes are currently recognised.[7][11]

References

  1. 1.01.1 Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012 Oct;136(10):1266-97 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22742517.
  2. 2.02.12.2 Darragh TM, Colgan TJ, Cox JT, Heller DS, Henry MR, Luff RD, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 2012 Jul;16(3):205-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22820980.
  3. Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, et al. The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol 2013 Jan;32(1):76-115 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23202792.
  4. Kurman, RJ (ed). World Health Organization classification of tumours of female reproductive organs. Lyon, France: International Agency for Research on Cancer; 2014 Available from: http://www.ncbi.nlm.nih.gov/nlmcatalog/101656343.
  5. Royal College of Pathologists of Australasia. Royal Australian College of Pathologists of Australasia Cervical Cancer Structured Reporting Protocol. [homepage on the internet]; 2013 [cited 2015 Dec 20]. Available from: https://www.rcpa.edu.au/getattachment/dbd9a178-b57e-4651-b6f8-9a52cf2c8900/Protocol-Cervical-cancer.aspx.
  6. McIlwaine P, Nagar H, McCluggage WG. Multifocal FIGO stage 1A1 cervical squamous carcinomas have an extremely good prognosis equivalent to unifocal lesions. Int J Gynecol Pathol 2014 May;33(3):213-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24681729.
  7. 7.07.17.27.3 Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO Classification of Tumours of Female Reproductive Organs. Lyon: IARCInternational Agency for Research on Cancer; 2014 Available from: http://apps.who.int/bookorders/anglais/detart1.jsp?codlan=1&codcol=70&codcch=4006.
  8. Zaino RJ. Glandular lesions of the uterine cervix. Mod Pathol 2000 Mar;13(3):261-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10757337.
  9. 9.09.1 McCluggage WG. Endocervical glandular lesions: controversial aspects and ancillary techniques. J Clin Pathol 2003 Mar;56(3):164-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12610091.
  10. McCluggage WG. New developments in endocervical glandular lesions. Histopathology 2013 Jan;62(1):138-60 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23134447.
  11. Young RH, Clement PB. Endocervical adenocarcinoma and its variants: their morphology and differential diagnosis. Histopathology 2002 Sep;41(3):185-207 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12207781.
Back to top