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CC BY 4.0 · Rev Bras Ginecol Obstet 2019; 41(02): 133-134
DOI: 10.1055/s-0039-1678591
Letter to the Editor
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

Comments on: Limitations of HPV DNA Testing in Screening of Cervical Adenocarcinomas

Marcos Emanuel de Alcântara Segura 
1   Lâmina Laboratory of Pathology and Cancer Prevention, Brasília, DF, Brazil
› Author Affiliations
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Address for correspondence

Marcos Emanuel de Alcântara Segura, MD, MSc.
Laboratório Lâmina de Patologia e Prevenção do Câncer
SGAS 915, 70390-150, Ed Office Center, Bloco A, Sala 11, Brasília, DF
Brazil   

Publication History

Publication Date:
20 February 2019 (online)

 
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Dear Editor,

I read with great interest the article on HPV DNA testing for cervical cancer screening in Brazil, authored by the Brazilian Association for the Lower Genital Tract Pathology and Colposcopy (ABPTGIC, in the Portuguese acronym).[1] In agreement with the authors, I have found irrefutable evidence sustaining the use of molecular detection of HPV DNA in this setting. However, every method, no matter how innovative or advanced, has limitations. The “Achilles' heel” of HPV DNA primary screening is the detection of glandular lesions. I found that the manuscript by the ABPTGIC tangentially addressed this issue.

An international cross-sectional study found that 38% of adenocarcinomas were not HPV-related.[2] A recently proposed histologic classification of endocervical adenocarcinoma, known as International Endocervical Adenocarcinoma Criteria and Classification (IECC),[3] uses the presence of HPV-related disease to histologically classify cervical adenocarcinomas. Among nonhuman papillomavirus-associated adenocarcinoma (NHPVA), the authors identify the following histological types: endometrial, gastric-type, minimal deviation, serous, clear-cell and mesonephric. In our practice, we have recently been involved in the case of an asymptomatic woman, HPV DNA-negative, who showed abnormal cytologic results interpreted as high-grade lesion. The patient proved to have a cervical clear-cell adenocarcinoma. This tumor is classified by the IECC group as a NHPVA and would not be identified in the screening scenario by molecular assays based on HPV DNA.

In summary, it is well recognized that HPV DNA detection delivers high sensibility, which is of great help, since cytologic-based screening is known to have low sensibility and high false-negative rates.[4] [5] But the limitations of this molecular detection should be recognized, such as the great proportion of NHPVAs. If molecular testing for HPV DNA is to be used as a primary screening test, one must acknowledge that non-HPV-related tumors would be missed.

Authors' Reply

Dear Editor,

The letter to the Editor “Limitations of HPV DNA testing in screening of cervical adenocarcinomas” mentioned the cross-sectional study of de Sanjose et al,[1] who found that more than one third of invasive cervical cancer adenocarcinomas are HPV-negative. In this way, an HPV DNA-based screening program would be ineffective in detecting those lesions. We agree that screening with this test would have some limitations and maybe this was not properly highlighted in our paper.

Screening as a public health program is designed to identify individuals at risk of developing a specific condition with high prevalence or health relevance. The vast majority of cervical cancers are HPV-positive squamous cell carcinomas, the main target of a cervical cancer screening program. The incidence of endocervical adenocarcinomas has been proportionally increasing due to expansion of screening, particularly in population-based programs.[2] In the study by Stolnicu et al[3], HPV-negative adenocarcinomas were diagnosed in more advanced stages than squamous carcinomas. Further studies are needed to clarify if this was due to later detection or a more aggressive behavior of the tumor. If the latter option was the case, screening would be less effective anyway.

The strongest evidence about the efficacy of HPV DNA-based screening comes from Ronco et al[4] in an extended follow-up of 4 randomized controlled trials with 176,464 women enrolled. The authors have found a greater protection against invasive cervical carcinoma using HPV DNA test compared with cytology. One of the most expressive results was the improvement in adenocarcinoma detection, showing that HPV DNA-based screening may improve the cytology-based programs deficiency in detecting glandular lesions.[5]

We recognize that one of the biggest challenges of cervical cancer screening is glandular lesions, especially because of its partially unknown natural history and probably less frequent association with HPV. More efforts should be addressed to improve the diagnosis of HPV-negative adenocarcinomas. However, considering the best available evidence until now, its effectiveness still allows us, as well as other authors and institutions, to recommend the use of these tests in cervical cancer screening in specific scenarios.


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Conflicts of Interest

The author reports no conflicts of interest whether political, economic, of resources for research execution or intellectual property.

  • References

  • 1 Zeferino LC, Bastos JB, Vale DBAPD. , et al. Guidelines for HPV-DNA testing for cervical cancer screening in Brazil. Rev Bras Ginecol Obstet 2018; 40 (06) 360-368 Doi: 10.1055/s-0038-1657754
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 de Sanjose S, Quint WG, Alemany L. , et al; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11 (11) 1048-1056 Doi: 10.1016/S1470-2045(10)70230-8
    CrossrefPubMedGoogle Scholar
  • 3 Stolnicu S, Barsan I, Hoang L. , et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42 (02) 214-226 Doi: 10.1097/PAS.0000000000000986
    CrossrefPubMedGoogle Scholar
  • 4 Nanda K, McCrory DC, Myers ER. , et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000; 132 (10) 810-819 Doi: 10.7326/0003-4819-132-10-200005160-00009
    CrossrefPubMedGoogle Scholar
  • 5 Cuzick J, Clavel C, Petry KU. , et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119 (05) 1095-1101
    CrossrefPubMedGoogle Scholar

    • References

    • 1 de Sanjose S, Quint WG, Alemany L. , et al; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11 (11) 1048-1056 Doi: 10.1016/S1470-2045(10)70230-8
      CrossrefPubMedGoogle Scholar
    • 2 Bucchi L, Baldacchini F, Mancini S. , et al. Estimating the impact of an organised screening programme on cervical cancer incidence: a 26-year study from northern Italy. Int J Cancer 2018 •••;. Doi: 10.1002/ijc.31806
      CrossrefPubMedGoogle Scholar
    • 3 Stolnicu S, Barsan I, Hoang L. , et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42 (02) 214-226 Doi: 10.1097/PAS.0000000000000986
      CrossrefPubMedGoogle Scholar
    • 4 Ronco G, Dillner J, Elfström KM. , et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383 (9916): 524-532 Doi: 10.1016/S0140-6736(13)62218-7
      CrossrefPubMedGoogle Scholar
    • 5 Andrae B, Kemetli L, Sparén P. , et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst 2008; 100 (09) 622-629 Doi: 10.1093/jnci/djn099
      CrossrefPubMedGoogle Scholar

Address for correspondence

Marcos Emanuel de Alcântara Segura, MD, MSc.
Laboratório Lâmina de Patologia e Prevenção do Câncer
SGAS 915, 70390-150, Ed Office Center, Bloco A, Sala 11, Brasília, DF
Brazil   

  • References

  • 1 Zeferino LC, Bastos JB, Vale DBAPD. , et al. Guidelines for HPV-DNA testing for cervical cancer screening in Brazil. Rev Bras Ginecol Obstet 2018; 40 (06) 360-368 Doi: 10.1055/s-0038-1657754
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 de Sanjose S, Quint WG, Alemany L. , et al; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11 (11) 1048-1056 Doi: 10.1016/S1470-2045(10)70230-8
    CrossrefPubMedGoogle Scholar
  • 3 Stolnicu S, Barsan I, Hoang L. , et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42 (02) 214-226 Doi: 10.1097/PAS.0000000000000986
    CrossrefPubMedGoogle Scholar
  • 4 Nanda K, McCrory DC, Myers ER. , et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med 2000; 132 (10) 810-819 Doi: 10.7326/0003-4819-132-10-200005160-00009
    CrossrefPubMedGoogle Scholar
  • 5 Cuzick J, Clavel C, Petry KU. , et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119 (05) 1095-1101
    CrossrefPubMedGoogle Scholar

    • References

    • 1 de Sanjose S, Quint WG, Alemany L. , et al; Retrospective International Survey and HPV Time Trends Study Group. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 2010; 11 (11) 1048-1056 Doi: 10.1016/S1470-2045(10)70230-8
      CrossrefPubMedGoogle Scholar
    • 2 Bucchi L, Baldacchini F, Mancini S. , et al. Estimating the impact of an organised screening programme on cervical cancer incidence: a 26-year study from northern Italy. Int J Cancer 2018 •••;. Doi: 10.1002/ijc.31806
      CrossrefPubMedGoogle Scholar
    • 3 Stolnicu S, Barsan I, Hoang L. , et al. International Endocervical Adenocarcinoma Criteria and Classification (IECC): a new pathogenetic classification for invasive adenocarcinomas of the endocervix. Am J Surg Pathol 2018; 42 (02) 214-226 Doi: 10.1097/PAS.0000000000000986
      CrossrefPubMedGoogle Scholar
    • 4 Ronco G, Dillner J, Elfström KM. , et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383 (9916): 524-532 Doi: 10.1016/S0140-6736(13)62218-7
      CrossrefPubMedGoogle Scholar
    • 5 Andrae B, Kemetli L, Sparén P. , et al. Screening-preventable cervical cancer risks: evidence from a nationwide audit in Sweden. J Natl Cancer Inst 2008; 100 (09) 622-629 Doi: 10.1093/jnci/djn099
      CrossrefPubMedGoogle Scholar

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