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Microinvasive Carcinoma of the Cervix: Site of First Focus of Invasion

From the Department of Obstetrics and Gynecology, University of Graz, Graz, Austria.

Address reprint requests to: Olaf Reich, MD Department of Obstetrics and Gynecology University of Graz Auenbruggerplatz 14 A-8036 Graz Austria E-mail: olaf.reich{at}kfunigraz.ac.at

	Abstract

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Objective: To evaluate the topography of the first invasive focus in microinvasive squamous cell carcinoma of the uterine cervix.

Methods: We studied 120 formalin-fixed and paraffin-embedded cold-knife conization specimens processed as step-serial sections. Four types of microinvasion were distinguished according to site: type I (ectocervical outside the last cervical gland), type II (ectocervical between the external os and the last gland and in connection with the surface epithelium), type III (ectocervical between the external os and the last gland but deep in cervical glands), and type IV (intracervical and in connection with the surface epithelium).

Results: A total of 142 early invasive foci were seen in the 120 cones. A single focus was seen in 106 (88%) specimens, whereas 14 (12%) had more than one focus. The foci were classified as type I in 16 (11%), type II in 31 (22%), type III in 70 (49%), and type IV in 25 (18%) cases.

Conclusion: One half of the early invasive foci originated at the surface epithelium (types I, II, IV), either at the ectocervix (types I, II) or in the endocervix (type IV).

Invasion of cervical squamous cell carcinoma begins from the basal layer of a field of cervical intraepithelial neoplasia (CIN) on the ectocervix, in the cervical canal, or in a cervical gland. A previous study of 81 conization specimens with microinvasive squamous cell carcinoma at our institution found that 72% of early invasive foci were localized within the ectopic area of the glandular field on the ectocervix.¹ Clement and Scully² reported that up to 90% of all squamous cell carcinomas start in the glandular area. Burghardt³ distinguished three latency periods in the natural history of cervical microinvasive cancer. The first latency period is between the appearance of intraepithelial neoplasia and the first invasive breakthrough into the cervical stroma and the second between this very first breach of the basement membrane and the formation of recognizable buds. The third latency period ends when the small buds establish themselves as entities capable of further spread. In the present study, we analyzed the location of the early invasive foci in microinvasive squamous cell carcinoma at time between first and second latency periods, characterized by the very first finger-like invasive foci. Invasive buds are still absent.^3,4

	Materials and Methods

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We studied 120 conization specimens with microinvasive squamous cell carcinoma of the uterine cervix diagnosed at our institution between 1972 and 2000. The median age of the patients was 38 years (range 22–70). Cones were obtained with a cold-knife technique. After fixation, the cones were halved in the sagittal plane and each half was embedded in paraffin so that the topography of the lesion and cervical structures was preserved. The paraffin blocks were processed as 200-µm–thick serial sections and stained with hematoxylin and eosin. An average of 90 sections were obtained per cone.

The estimated positions of the external os, the so-called last cervical gland^4,5 and the site of the early invasive foci were noted and marked on the histologic slides (Figure 1). All slides were evaluated by two gynecologic pathologists (H.P. and O.R.). All early microinvasive carcinomas had a finger-like growth pattern. Invasive buds were still absent. Early invasive foci were diagnosed by the stromal reaction to invasion (ie, a loose stroma infiltrated by round cells).^3,4,6

View larger version (130K): [in this window] [in a new window]   Figure 1. Anatomical landmarks of four topographical types of microinvasion. The conization specimen shows a large squamous in situ carcinoma on the right. The carcinoma in situ extends from the outer third of the ectocervix deep into the cervical canal and extensively involves dilated cervical glands. We distinguished four topographical types of microinvasion: type I: ectocervical outside the last cervical gland (I); type II: ectocervical between the external os and the last gland and in connection with the surface epithelium (II); type III: ectocervical between the external os and the last gland but deep in cervical glands (III); and type IV: intracervical and in connection with the surface epithelium (IV). L.G. = last cervical gland; E.O. = external os.

	Results

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A total of 142 early invasive foci were seen in the 120 cones. A single focus was seen in 106 (88%) cases and more than one focus in 14 (12%). The foci were classified as type I in 16 (11%), type II in 31 (22%), type III in 70 (49%), and type IV in 25 (18%) cases (Figure 1).

	Discussion

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In our study one half of the early invasive foci arising from CIN originated at the surface epithelium (types I, II, IV), either at the ectocervix (types I, II) or in the endocervix (type IV). The other half of the foci originated within cervical glands without connection to the surface (type III) (Figure 1). The differentiation between these types is important because lesions of the squamous epithelium outside the transformation zone, that is, outside the area of the previous ectopy (type I), develop by direct transformation of the original squamous epithelium. In contrast, types II, III, and IV develop via squamous metaplasia of the columnar epithelium.^4,7 The distal extent of the former ectopy is marked by the last gland,^4,5 which is an anatomic marker as well as the focal point for the distribution of the stromal connective tissue and blood vessels of the outer area of the cervix.⁴ However, in our study, type I lesions were infrequent, and 89% of all early invasive carcinomas started from the glandular area (type II, III, IV). This is consistent with the results reported by Clement and Scully.²

Our results suggest that not all microinvasive lesions of the cervix are amenable to early diagnosis and that multicentricity with early invasive foci at numerous sites can occur. Type I and II lesions are well accessible to colposcopy and cytology. Type III lesions, which orginate within the cervical gland field, sometimes several millimeters below the surface, can remain hidden from colposcopy until they establish a relationship to the surface of the ectocervix and show a microexophytic surface contour at colposcopy. Type IV lesions are well above the external os and thus not accessible to colposcopy. Microcolpohysteroscopy may be a technique to inspect the surface of these intracervical lesions.⁸

There may have been an element of selection bias in our series in that it included only cases with early invasion. It may be that CIN on the ectocervix is detected (and treated) earlier in its natural history, so that cases that progress to microinvasion are more likely to be further away from the ectocervix than those that are detected earlier.

These anatomic results regarding the location of early invasion are relevant to ablative modalities (laser vaporization, cryocoagulation, diathermy) used to treat cervical neoplasia thought to be limited to the epithelium. These methods are performed under colposcopic guidance.^9–12 Before treatment, clinicians want to minimize the risk of missing microinvasion by taking multiple punch biopsies. However, the sites at which early invasive disease can develop mean that not all microcarcinomas will be amenable to early diagnosis with colposcopy and biopsy.¹³ Paraskevaidis et al¹⁴ reported the sensitivity of colposcopy for detecting microcarcinomas was only 50% in a series of 61 cases. In 34% of patients, both cytology and colposcopy were nonsuspicious. Murdoch et al¹⁵ demonstrated that accurate colposcopic detection of microinvasive carcinoma requires invasion exceeding 1 mm into the cervical stroma. In this study,¹⁵ only six (33%) of 18 patients with stage IA disease had satisfactory colposcopy. We believe that only excisional techniques (cold-knife conization, large loop excision of the transformation zone, laser conization) are adequate to diagnose or rule out early invasion.

	Footnotes

 
PII S0029-7844(01)01358-8

Received October 5, 2000. Received in revised form January 4, 2001. Accepted February 15, 2001.

	References

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1. Pickel H, Burghardt E. On the location of beginning invasive cancer of the cervix. Arch Gynäkol 1973;215:187–98.[Medline]

2. Clement PB, Scully RE. Carcinoma of the cervix: Histologic types. Sem Oncol 1982;9:251–64.[Medline]

3. Burghardt E. Diagnostic and prognostic criteria in cervical microcarcinoma. Clin Oncol 1982;1:123–33.

4. Burghardt E. Histopathology of the cervical epithelium. In: Burghardt E, Pickel H, Girardi F, eds. Colposcopy, cervical pathology. Textbook and atlas. 3rd ed. Stuttgart: Thieme, 1998:9–56.

5. Hamperl H, Kaufmann C. The cervix uteri at different ages. Obstet Gynecol 1959;14:621–31.[Medline]

6. Burghardt E. Early stromal invasion: Histopathology. In: Burghardt E, Webb MJ, Monaghan JM, Kindermann G, eds. Surgical gynecologic oncology. Stuttgart: Thieme, 1993:188–201.

7. Burghardt E, Holzer E. Treatment of carcinoma in situ: Evaluation of 1609 cases. Obstet Gynecol 1980;55:539–44.[Abstract/Free Full Text]

8. Hamou J, Salat-Barouy J, Coupez F, De-Brux J. Microhysteroscopy: A new approach to the diagnosis of cervical intraepithelial neoplasia. Obstet Gynecol 1984;63:567–74.[Abstract/Free Full Text]

9. Guerra B, De-Simone P, Gabrielli S, Falco P, Montanari G, Bovicelli L. Combined cytology and colposcopy to screen for cervical cancer in pregnancy. J Reprod Med 1998;43:647–53.[Medline]

10. Van-Rooijen M, Persson E. Pregnancy outcome after laser vaporisation of the cervix. Acta Obstet Gynecol Scand 1999;78:346–8.[Medline]

11. Adewole IF, Babarinsa IA, Odeniyi GD. Cryotherapy in the management of cervical intraepithelial neoplasia in developing countries. Int J Gynecol Obstet 1998;60:69–70.[Medline]

12. Cirisano FD. Management of preinvasive disease of the cervix.Sem Surg Oncol 1999;16:222–7.[Medline]

13. Herzog TJ, Williams S, Adler LM, Rader JS, Kubiniec RT, Camel HM, Mutch DG. Potential of cervical electrosurgical excision procedure for diagnosis and treatment of cervical intraepithelial neoplasia. Gynecol Oncol 1995;57:286–93.[Medline]

14. Paraskevaidis E, Kitchener HC, Miller ID, Mann E, Jandial C, Fisher PM. A population-based study of microinvasive disease of the cervix—a colposcopic and cytologic analysis. Gynecol Oncol 1992;45:9–12.[Medline]

15. Murdoch JB, Grimshaw RN, Morgan PR, Monaghan JM. The impact of loop diathermy on management of early invasive cervical cancer. Int J Gynecol Cancer 1992;2:129–33.[Medline]

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