Two major pathways of recurrent high‐grade squamous intraepithelial lesions of the cervix

Abstract

Dear Sir,We read with interest the article by Herfs et al. 1 reporting the outcome of 131 consecutive patients with SIL after electrosurgical excision procedure (LEEP) during a mean follow-up period of 1.7 (0.4-3.5) years. About 94.3% of patients had high-grade squamous intraepithelial lesions (HSIL) at time of primary treatment. In four patients with positive resection margins in their initial cone specimen, HSIL was detected after 3 months and interpreted as persistent disease. Both primary and persistent lesions were positive for so called squamo-columnar junction (SCJ) makers. Twelve women with complete resection of their initial HSIL developed a low-grade squamous intraepithelial lesion (LSIL) negative for SCJ markers. Herfs et al. 1 propose that HSIL/invasive cervical cancer arise from a small cell population at the SCJ whereas high-risk human papillomavirus (HR-HPV) infection of the original squamous epithelium and metaplastic squamous epithelium of the transformation zone (TZ) usually produces a primary or recurrent LSIL, and that a prophylactic destruction of SCJ may be an effective prevention of SCC.In our opinion, this study has two major problems: Firstly, the short follow-up and the low number of patients reported by Herfs et al. 1 are serious limitations which may account for the absence of recurrent HSIL, adenocarcinoma in situ (AIS) and invasive cervical cancer after LEEP in their series. The short observation time may be responsible for some underreporting of recurrent HSIL and does not allow the postulation of a unique recurrence pattern of squamous intraepithelial lesion (SIL) following excision of the SCJ, in particular since the results of their study contradicts those of observations with long follow-up. In a longterm study of 4,417 patients with cervical intraepithelial neoplasia (CIN) 3 after cold knife conization (CKC) with clear margins, 15 (0.35%) women developed a new HSIL after a median follow-up of 107 months (range 40-201). AIS developed in 2 (0.05%) patients 14 and 17 years after conization. 2 In another long-term follow-up study on 390 patients with cervical intraepithelial neoplasia (CIN) 3 and involved margins after CKC, 306 (78%) patients remained free of CIN 3, and 84 (22%) had persisting or recurrent CIN 3 (n 5 78) or developed invasive carcinoma (n 5 6). Fifty-three of the 84 patients had persisting CIN 3 (diagnosed within 1 year of conization), 25/84 developed recurrent CIN 3 after a median of 3 (range 2-28) years, 5/84 developed microinvasive carcinomas (at 3, 6, 7, 12 and 23 years), and 1/84 developed a FØGO stage IB carcinoma at 8 years. 3 HSIL can be treated by different techniques, including ablative techniques (e.g., cryosurgery, electrocautery, cold coagulation or laser ablation) and excisional techniques (e.g., largeloop excision of the transformation zone (LLETZ) or CKC). When excisional techniques were compared, recurrent HSIL has been reported after LLETZ up to 30 times higher than after CKC, most likely as a result of less aggressive treatments in the last two ...

Switches of SOX17 and SOX2 expression in the development of squamous metaplasia and squamous intraepithelial lesions of the uterine cervix

“…6 The comparable SOX17 expression patterns in reserve cells and in the remnants of IMM support the general opinion that reserve cells are the progenitors for IMM and may therefore provide additional evidence for the reserve cell as the progenitor of cervical (pre)neoplasia. 13,22,43,45 The reserve cells, in turn, are suggested to originate from either the basal cells of the squamous epithelium 14,46 or from the stretch of cuboidal cells at the SqCJ recognized by Herfs et al 15 Although we did not specifically recognize these stretches of cuboidal cells in our tissue samples, it is very likely that these latter cells are also SOX17 positive.…”

“…5,16,26,41 The debate about the cells of origin for these lesions is, however, still ongoing. 15,16,42,43 Neoplasia in the cervix is suggested to occur at particular epithelial sites, where vulnerable cells, such as the reserve cells or cuboidal cells, are found. 14,15 The underlying study focuses on SOX2 and SOX17 expression during (pre)neoplastic transformation of the uterine cervix.…”

“…24,41,47,48 A second theory states that HSIL is the result of a hrHPV infection of IMM, as concluded from the dual expression of keratin 17 and p16 in atypical squamous lesions with metaplastic features. 6,13,22,43,45 The third pathway involves hrHPV infection of the specific stretch of endocervical, keratin 7-positive cuboidal cells at the SqCJ, producing immediately a HSIL without a low-grade precursor lesion. 4,5 Our results support the view that IMM, originating from reserve cells is the target for hrHPV and as a result the origin of HSIL, concluded from the fact that we found a switch from SOX17-positive and SOX2-negative areas of squamous epithelium (IMM) to SOX17-negative and SOX2-positive HSIL which were in direct connection with each other (Figures 5 and 6C).…”

Response to “Two major pathways of recurrent high‐grade squamous intraepithelial lesions of the cervix”

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The authors list two criticisms in their letter. 1 The first is that the follow-up period in this study was not long enough to appreciate potential new infections that could result in high grade cervical intraepithelial neoplasia (CIN) despite the presumed excision of the squamocolumnar (SC) junction. The second is that reserve cells are important progenitors of preinvasive squamous lesions of the cervix and because of their wider distribution they cannot be excised surgically.Concerning the first criticism, the authors describe studies from their institution that reported a recurrent CIN3 or adenocarcinoma in situ in less than 4 women per 1,000 treated by excision for CIN3 with negative margins, in contrast to 22% of those with positive margins.

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“…The authors list two criticisms in their letter. 1 The first is that the follow-up period in this study was not long enough to appreciate potential new infections that could result in high grade cervical intraepithelial neoplasia (CIN) despite the presumed excision of the squamocolumnar (SC) junction. The second is that reserve cells are important progenitors of preinvasive squamous lesions of the cervix and because of their wider distribution they cannot be excised surgically.…”