It has been clearly established through decades of research that the occurrence of cervical cancer is closely related to high-risk HPV infection. With the widespread implementation of cervical cancer screening, the incidence of cervical cancer has been significantly reduced and many early cervical cancers and precancerous lesions have been detected, and accurate pathological diagnosis and classification are crucial for the next step of clinical treatment and management. In recent years, there have been some changes in the nomenclature and classification of cervical precancerous lesions, and this article will focus on these changes and their impact on pathological diagnosis and clinical management.
It has been clearly established through decades of research that the occurrence of cervical cancer is closely related to high-risk HPV infection. With the widespread implementation of cervical cancer screening, the incidence of cervical cancer has been significantly reduced and many early cervical cancers and precancerous lesions have been detected, and accurate pathological diagnosis and classification are crucial for the next step of clinical treatment and management. In recent years, there have been some changes in the nomenclature and classification of cervical precancerous lesions, and this article will focus on these changes and the impact on pathological diagnosis and clinical management.
I. Cervical squamous epithelial precancerous lesions
Currently, the most widely used term for cervical squamous cell precancerous lesions is cervical intraepithelial neoplasia (CIN), and it is classified into three levels, i.e., CIN1, CIN2 and CIN3, of which CIN3 includes the former squamous epithelial hyperplasia with in situ carcinoma in situ (CIN3). (carcinoma in situ, CIS), a nomenclature system designed to describe the continuum of morphologic changes in the cervical squamous epithelium from abnormal hyperplasia to carcinoma.
It has been applied for more than 10 years since the WHO classification was formally introduced in 2003. Although the CIN nomenclature system has better guided the next step of clinical management, some problems have been found in the application. First, the diagnostic terminology of CIN defines it as neoplasia, which means that it is considered a neoplastic lesion regardless of its classification. However, in fact, a significant proportion of squamous epithelial lesions caused by HPV infection are transient (e.g., CIN grade 1 lesions), and most of them are self-limiting and regressive. Therefore, it is inappropriate to call them “neoplastic lesions”, especially when the clinician and the patient do not understand the true nature of the lesion, which may lead to overtreatment and unnecessary emotional burden for the patient.
Secondly, the repeatability of CIN grade 2 lesions in pathological diagnosis is poor, which means that there is a large variability in the diagnosis of CIN grade 2 lesions between different pathologists or between the same physician at different times (low kappa values). In addition, from the current standardized clinical process of cervical lesion management, patients with CIN1 need only follow-up observation, while patients with CIN2 or higher need to be treated clinically accordingly.
In terms of cytologic screening diagnosis, the grading system for cervical cytology smears (Bethesda system) uses a two-level classification for squamous epithelial lesions.
Based on these considerations, there has been a gradual international trend in recent years to adopt a simpler two-level classification for the description and diagnosis of cervical squamous epithelial precancerous lesions, and in 2012 the American Academy of Pathology (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) jointly published a standardized plan for the nomenclature of HPV-associated squamous lesions of the lower genital tract (The Lower The Lower Anogenital Squamous Terminology Standardization Projectfor HPVAssociated Lesions (LAST Project), in which a revised nomenclature for squamous epithelial lesions associated with HPV infection in the lower genital tract, including the cervix, is proposed. Squamous intraepithelial lesion (SIL) is the recommended nomenclature.
The fourth edition of the WHO Classification of the Female Genital System published in 2014 The WHO classification of the female reproductive system adopts this nomenclature scheme for cervical squamous cell precancerous lesions, where synonyms for LSIL include cervical intraepithelial neoplasia grade I (CIN1), mild atypical hyperplasia, lichen planus, and excavated cell disease, while synonyms for HSIL include cervical intraepithelial neoplasia grade II (CIN2), cervical intraepithelial neoplasia grade III (CIN3 ), moderate atypical hyperplasia, severe atypical hyperplasia, and squamous epithelial carcinoma in situ.
Such a two-level classification scheme for squamous intraepithelial lesions is simple and practical, allowing for a more reproducible pathologic diagnosis, and also allows for histologic grading to correspond with cytologic grading. More importantly, the classification scheme better reflects the biological process of HPV-related lesions and can better guide clinical management and prognostic judgment.
About 80% of LSIL is caused by high-risk HPV infection (HPV types 16 and 18 mainly), and the remaining cases are low-risk HPV infections (HPV types 6 and 11), and most cases are transient infections. A large number of retrospective studies have shown that the overall prognosis of biopsy-proven LSIL is good, and most cases will disappear within one year; while more than 90% of the cases in HSIL More than 90% of cases of HSIL are infected with high-risk HPV, and data show that about 1/3 of HSIL can progress to cancer within 30 years without appropriate treatment. Thus, a pathological diagnosis of LSIL can be followed up without surgical removal of the cervix, whereas HSIL requires clinical treatment.
Although the new nomenclature and classification has the above advantages, it is important to note that in the LAST program, CIN2 lesions are not simply classified as HSIL, as many previously diagnosed CIN2 lesions contain part of LSIL and part of HSIL. The p16 is a cell cycle protein-dependent protein.
p16 is a cell cycle protein-dependent kinase inhibitor involved in the regulation of the cell cycle. In high-grade lesions due to persistent HPV infection p16 shows continuous large dark brown staining, whereas in low-grade lesions p16 can be negative, or confined to intermediate and superficial layers, thus p16 immunohistochemical staining is recommended in the following pathological diagnostic situations.
(i) when the pathologic diagnosis requires identification of HSIL or immature squamous, atrophic, reparative epithelial hyperplasia and other tumor-like lesions;
②When CIN2 lesions are considered on pathological histology;
(iii) when there is a possibility of high-risk lesions on cytology or HPV testing, but no obvious lesions are found on histology.
In addition, although hysterectomy is performed for most HSIL in clinical management, it is not necessary to perform hysterectomy for young women, especially those who have not completed childbirth, because it involves preservation of reproductive function and studies have shown that some CIN2 may regress, so it is still clinically relevant to distinguish between CIN2 and CIN3 in the pathological diagnosis. At this stage, it is recommended that both nomenclature schemes be listed in the pathology report, such as HSIL (CIN2) or HSIL (CIN3), in order to facilitate individualized clinical treatment.
Cervical adenopathy
With the increase in the number of cervical lesions and the expansion of cervical lesion screening, cervical adenocarcinoma has become a growing concern. 2003 third edition of WHO classification named the precursor lesions of cervical glandular epithelium as Endocervical glandular dysplasia (EGD) and adenocarcinoma in situ ( Adenocarcinoma in situ (AIS), some scholars name the pre-infiltrative lesions as Cervical glandular intraepithelial neoplasia (CGIN), some classify them into three grades: CGIN1, CGIN2 and CGIN3, and some classify them There are two levels of CGIN: low grade CGIN (LCGIN) and high grade CGIN (HGCGIN).
In 2014, the 4th edition of WHO classification has been adjusted for the nomenclature of glandular epithelial precursor lesions. Only adenocarcinoma in situ (AIS) is included among the precursor lesions and is defined as an intraepithelial lesion with a malignant presentation that, if left untreated, has a significant risk of progression to invasive adenocarcinoma.
A synonymous name is high-grade CGIN (HGCGIN), whereas endocervical glandular atypia or low-grade CGIN in the third edition is not listed separately in this classification, but is only mentioned in the AIS, and it is noted that this type of lesion, due to poorly defined diagnostic criteria and reproducibility, is not yet treated further in the clinic.
If such lesions are seen in pathological biopsies, p16, Ki67, ER and PR immunohistochemical staining can be added. When the lesions show clear diffuse positive p16, high Ki67 proliferation index and lack of estrogen and progesterone receptor expression, they are considered to be morphologically incomplete AIS and should be treated clinically according to AIS. The new WHO classification has introduced a new lesion in AIS: stratified mucinproducing intraepithelial lesion (SMILE), which is a variant of AIS and should be treated clinically as AIS (Table 2).
From the clinical treatment point of view, in cases with a clear diagnosis of AIS on pathological biopsy, a Leep or cone excision should be performed and sent to pathology for complete examination, which should be taken at 12 consecutive points, paying attention to whether the lesion is multipoint and jumping lesion and whether there is lesion involvement at the cut edge. Hysterectomy is recommended for women who have completed childbirth and no longer have a desire to have children. For patients treated conservatively, close follow-up including colposcopy, cytology and HPV testing should be performed.
In conclusion, the new nomenclature and classification changes regarding cervical precancerous lesions reflect the nature of cervical lesions more completely, simplify the grading, and propose some auxiliary diagnostic markers, which make the accuracy and reproducibility of pathological diagnosis improve and facilitate further clinical management. At this stage, when applying the new names and classifications, the names of traditional classifications should be indicated as far as possible. For example, when diagnosing SIL, the corresponding “IN” names and classifications should also be noted, so as to facilitate clinical understanding and mastery gradually.