Introduction

Superficial spreading squamous cell carcinoma (SCC) of the cervix is a rare phenomenon. The spread usually occurs by direct local extension, lymphatic embolization and by hematogenous dissemination. Direct extension to the lower uterine segment and/or endometrial cavity occurs in about 10% to 30% of patients [1]. However, the upward superficial contigous spread of endometrium and fallopian tube is much rare with fewer than 20 cases reported in literature.

Case Report

A 65-year-old post menopausal woman presented with foul smelling, white discharge per vagina since 1 month. The clinical diagnosis was cervical stenosis with pyometra. Cervical dilation was done and biopsies were obtained from cervix and endometrium. Microscopically, both cervix and endometrium showed severe squamous dysplasia. The patient subsequently underwent total hysterectomy with bilateral salpingo-oophorectomy. Grossly, the uterus with cervix measured 8 x 6 x 3 cm. On cut section, the endometrial cavity was dilated and exuded 15 ml of thick brown colour fluid. (Fig. 1) The cervix appeared unremarkable and the left fallopian tube on cutting exuded purulent material with dilated lumen.

Microscopically, the cervix showed squamous cell carcinoma in situ with moderate inflammation in the stroma. There was upward surface extension into isthmus with complete replacement of endometrial lining and left fallopian tube epithelium by carcinoma in situ. (Fig 2,3,4). The spread was contiguous and there was no stromal invasion in any of these sites. Immunohistochemistry with p16 showed diffuse, intense positivity of dysplastic stratified squamous epithelium in all the sites.

Fig 1: Specimen of uterus with dilated endometrial cavity	Fig 2: Cervix showing severe dysplasia (H&E x100, Inset- P16 overexpression IHC, x100)
Fig 3: Endometrium showing squamous cell carcinoma in situ (H&E x100, Inset- P16 overexpression IHC, x40)	Fig 4: Left side Fallopian tube showing carcinoma in situ (H&E x100, P16 overexpression IHC, x40)

Discussion

Cervical cancer continues to be a common malignancy affecting middle-aged women, particularly in less-resourced countries [2]. The primary routes of spread of cervical carcinoma are direct local extension and lymphatic embolization. The hematogenous dissemination usually occurs with more advanced disease or unusual cell types. Direct extension to the lower uterine segment and/or endometrial cavity occurs in about 10% to 30% of patients [1].

Cervical SCC that spreads superficially to the inner surface of the uterus replacing the endometrium with carcinoma cells is called superficial spreading SCC, which is a very rare phenomenon [3].

Baggish & Woodruff did a comprehensive literature search and presented a classification of histogenesis of squamous epithelium in the endometrium. They noted that the presence of squamous epithelium in endometrium occur in conditions varying from physiological as in endometrial shedding, non neoplastic conditions like foreign bodies, chronic inflammation etc, and underlying benign and malignant neoplasms. They emphasized on the careful study of each case in order to eliminate the possibility of extension of squamous cell carcinoma of cervix. They cited a case of cancer cervix with extension into endometrial surface and fallopian tube. They have also mentioned about the occurrence of a similar case in their laboratory. Since then, many cases of squamous cell carcinoma extending into the endometrium have been reported. Some authors are of the opinion that they were two cancers occurring simultaneously and were coincidental, while others attributed it to post radiotherapy treatment in diagnosed cases of cancer cervix [4].

Superficial spreading SCC of the cervix is a rare phenomenon, with few cases reported in literature. The search of English literature revealed contiguous spread of SCC cervix into endometrium and fallopian tubes in nineteen cases, out of which 8 cases showed involvement of ovaries. One case among them also showed omental deposits. (Table 1)

The main clinical manifestations include vaginal bleeding, pyometra, abdominal mass, lower abdominal pain, abnormal pap smears, hematometra, and excessive genital discharge. Our patient presented with foul smelling vaginal discharge and pyometra. In any postmenopausal woman with pyometra, if widespread keratinization of endometrial surface is detected in the curettage or biopsy, then careful examination should be done to rule out an underlying malignancy [3]. The pathology of cervical neoplasia varied from SCC in situ, invasive SCC, microinvasive SCC and the pattern of spread in the endometrium, fallopian tubes and ovaries were also in situ and invasive [5].

The diagnosis of superficial spreading SCC of the uterine cervix involving the endometrium requires careful examination of the uterine body and the cervix to rule out primary endometrial SCC. This is based on the following strict pathological criteria recommended by Fluhmann: (1) no evidence of a coexisting endometrial adenocarcinoma or primary cervical SCC (2) no connection between the endometrial tumour and squamous epithelium of the cervix; or (3) no connection between any existing cervical in situ carcinoma and the independent endometrial neoplasm. In the present case, we demonstrated the continuity of the cervical lesion to the endometrium and fallopian tube, conforming Fluhmann criteria [3,6].

Intraepithelial carcinoma of the vagina and endometrium are seen in association with cervical cancer at a frequency of 2.0% and 0.7% respectively [7]. The common patterns of uterine corpus involvement by cervical cancer are through deep myometrial penetration and lymphatic dissemination. The association of endometrial lesion in the presence of cervical cancer is usually assumed to result from a “horizontal spread” as postulated by Cullen and Ferenczy et al where cervical neoplastic cells mechanically displace and eventually replace the benign glandular epithelium of the endometrium. The second mechanism is a process in which the normal cell transforms to malignant cell, proliferates vertically (Field theory of carcinogenesis), with occurrence of carcinoma cervix and endometrium independently and concurrently by the same cancer stimulating agent. The superficial surface spread of in situ or invasive squamous carcinoma of cervix over the contiguous endometrial surface may be evident on gross inspection as whitish patches, a condition called "cake icing" or "Zuckerguss" carcinoma. [5,6,7]. Histological continuity between cervical, endometrial and fallopian tube lesion is often demonstrated as in the present case. Qizilbash proposed that the cervical stenosis and subsequent pyometra could have a promoting effect for surface propagation of cervical cancer. The mitotic activity is an essential criterion for the diagnosis of carcinoma in situ of the tube as proposed by Pauerstein & Woodruff. [6,8].

The World Health Organization (WHO) in its classification of tumors of the cervix and Federation of International Gynecologists & Obstetricians (FIGO) in cancer staging have not described such an event. It may be essential to include this phenomenon as occasional cases of superficial spreading SCC are reported with extension into bilateral fallopian tubes, ovaries and even spread to lymphnodes and omentum. However, the prognostic significance is lacking with the available limited data. The study of more cases are therefore needed to determine management guidelines and prognosis [3,9,10].

Pins MR et al investigated for the presence of HPV genome by PCR analysis and noted its presence in a case of cervical carcinoma in situ with spread to endometrium, bilateral fallopian tubes with focal invasion and bilateral ovarian surface and parenchyma. This supported the contiguous spread of tumor [11]. However, Kushima et al are of the opinion that the presence of HPV16 throughout the lesions does not necessarily support contiguous spread but rather consistent with a field effect by an infectious agent. They recommend genetic analysis to establish the monoclonality of such lesions. They described five cases of unusual superficial spread of cervical SCC and performed genetic analysis which suggested a single clonal process with frequent loss of heterozygosity of 6p, 6q, 11p and 11q. Thus, they indicated that these tumors originated from the cervix and extended superficially to the upper genital tract. We performed IHC with p16 and found the dysplastic epithelium to be diffusely and strongly positive in all the sites. We believe that dysplastic features on histology along with p16 as a surrogate marker for HPV would be of considerable value in establishing the origin of the tumor. A number of studies have demonstrated p16 to be a useful, robust, specific and sensitive biomarker marker for squamous and glandular epithelial dysplasia in the uterine cervix and appears to correlate with the degree of cervical neoplasia. This was explained in two ways: the most possible explanation for the composite of findings is that a HPV associated squamous cell dysplasia originated in the cervix and extended proximally in a purely lepidic pattern with surface extension or by colonizing a pre-existing ichthyosis uteri [5,12,13]. Some authors have described SCC of cervix with dysplastic epithelium in uterus as ichthyosis uteri showing dysplastic changes [14]. A strong expression of CD138 has been demonstrated in carcinoma cells that participate in superficial spreading by regulating cell to cell interactions while cells in the invasive focus lacking CD138 expression [5]. However, CD138 was not done in the present case.

Total abdominal hysterectomy with bilateral salpingo-oophorectomy is the optimal therapy for superficial spreading SCC, however, the available data are insufficient to evaluate the role of additional radiotherapy or chemotherapy [3,13].

Conclusion

Superficial spreading squamous cell carcinoma in situ of cervix with surface extension into endometrium and fallopian tube is rare and very few cases are reported. IHC with p16 may be used as a surrogate marker to establish the histogenesis. More cases are needed to understand the therapeutic and prognostic implications.

References

1. Gallup D. The Spread and Staging of Cervical Cancer. Glob.libr. Women’s med, (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10231. Available at https://www.glowm.com/section-view/heading/The%20Spread%20and%20Staging%20of%20Cervical%20Cancer/item/231
2. Arbyn M, Weiderpass E, Bruni L, Sanjose S, Saraiya M, Ferlay J. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. The Lancet of Global Health. 2020;8(2) DOI: https://doi.org/10.101: 6/S2214-109X(19)30482-6
3. Du Jing, Liao X. Case Report Superficial spreading squamous cell carcinoma in situ of the cervix involving the endometrium: a rare case presentation and review of literature. Int J Clin Exp Pathol 2019;12(11):4162-4166
4. Baggish MS, Woodruff JD. The occurrence of squamous epithelium in the endometrium. Obstet Gynecol Surg 1967;22:69–115.
5. Muthusamy RK, Mehta SS. Squamous cell carcinoma in situ of the cervix with superficial intraepithelial extension to the endometrium of lower uterine segment: a rare presentation. Indian J Med Paediatr Oncol 2017;38: 88-89.
6. Qizilbash A, DePedrillo A. Endometrial and tubal involvement by squamous carcinoma of the cervix. Am J Clin Pathol 1975;64: 668–71.
7. Kanbour AI, Stock RJ. Squamous cell carcinoma in situ of the endometrium and fallopian tube as superficial extension of invasive cervical carcinoma. Cancer 1978;42:570–80.
8. Punnonen R, Grönroos M and Vaajalahti P. Squamous cell carcinoma in situ from the uterine cervix to the distal end of the fallopian tube. Acta Obstet Gynecol Scand 1979;58: 101-104.
9. Motoyama T, Watanabe H. Squamous cell carcinoma of the cervix with extensive superficial spreading to almost whole genital tract and associated with endometrial stromal sarcoma. Acta Pathol Jpn 1988;38:1445–52.
10. Nakajima T, Hatta H, Nishida T, Minamisaka T, Miwa S, Terahata S, Imura J. Superficial spread of cervical squamous cell carcinoma to the upper genital tract and dissemination to the omentum. Pathol Int 2019;69:119-121.
11. Pins MR, Young RH, Crum CP, et al. Cervical squamous cell carcinoma in situ with intraepithelial extension to the upper genital tract and invasion of tubes and ovaries: report of a case with human papilloma virus analysis. Int J Gynecol Pathol 1997;16:272–8.
12. Lesnikova I, Lidang M, Hamilton-Dutoit S. et al. p16 as a diagnostic marker of cervical neoplasia: a tissue microarray study of 796 archival specimens. Diagn Pathol. 2009;4: 22. https://doi.org/10.1186/1746-1596-4-22
13. Kushima M, Fujii H, Murakami K, Ota H, Matsumoto T, Motoyama T, Kiyokawa T, Ishikura H. Simultaneous squamous cell carcinomas of the uterine cervix and upper genital tract: loss of heterozygosity analysis demonstrates clonal neoplasms of cervical origin. Int J Gynecol Pathol 2001;20:353-358.