I cell carcinomas of the endometrium and

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SQUAMOUS CELL CARCINOMA IN SITU OF THE ENDOMETRIUM AND FALLOPIAN TUBE AS SUPERFICIAL EXTENSION OF INVASIVE CERVICAL CARCINOMA ANISA I. KANBOUR, MD,* AND RICHARD J.

1 SQUAMOUS CELL CARCINOMA IN SITU OF THE ENDOMETRIUM AND FALLOPIAN TUBE AS SUPERFICIAL EXTENSION OF INVASIVE CERVICAL CARCINOMA ANISA I. KANBOUR, MD,* AND RICHARD J. STOCK, MDt Five cases of squamous cell carcinoma of the cervix associated with widespread squamous cell carcinoma in situ of the endometrial surface are reported. In one case, carcinoma in situ was also found in one fallopian tube in continuity with the cervicoendometrial lesion. A survey of the literature reveals only 2 cases with similar surface endometrial involvement by cervical squamous cell carcinoma. Of these, the fallopian tubes were involved by an identical lesion in six cases only. Pyometra and cervical stenosis were reported in about 66% of the cases. This rare form of upward cervical cancer extension was present in five of 68 cases (.7%) of squamous cell carcinoma of the cervix in the file of the Tumor Registry of MageeWomens Hospital. Cancer 42:5758, NTRAEPITHELIAL AND INVASIVE squamous I cell carcinomas of the endometrium and the Fallopian tube are very rare. Usually, these lesions are associated with intraepithelial or invasive squamous cell carcinoma of the cervix,1,11,19,26,27,28~3 although primary squamous cell carcinoma of the endometrium and of the Fallopian t~be ~,~O also occur. In the presence of cervical cancer, the usual assumption is that the endometrial lesion results from a horizontal spread where cervical neoplastic cells would mechanically displace and eventually replace the benign glandular epithelium of the end~metrium.~, However, a concommitant or sequential primary squamous cell carcinoma of the endometrium independent of the cervical cancer may arise through squamous metaplasia of the endo metrial epithelial surface.8,2 Squamous metaplasia of the endometrium has been reported in association with various conditions including vitamin A deficiency, endogenous or exogenous estrogen, chronic endometritis, tuberculosis or syphilis, chronic inversion, radiation, foreign bodies, chemical reaction and pyometra. From the *Department of Pathology, MageeWomens Hospital, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, and?washington Adventist Hospital, Takoma Park, Maryland. Address for reprints: Anisa I. Kanbour, MD, Department of Pathology, MageeWomens Hospital, Forbes Avenue & Halket Street, Pittsburgh, PA The authors thank Hernando Salazar, MD, and Vida Peterson for assistance. Accepted for publication December 3, X An interesting case of squamous cell carcinoma of the cervix in which there was replacement of the entire endometrial surface by an intraepithelial squamous neoplasm with extension into the Fallopian tube stimulated us to undertake this study to determine the frequency of endometrial surface involvement by squamous cell carcinoma of the cervix and to evaluate the clinicopathological contributory factors. Five such cases were studied. MATERIALS AND METHODS Six hundred eighty cases of carcinoma of the cervix were reviewed from the files of the MageeWomens Hospital Tumor Registry from 1965 to In five cases, including the one mentioned above, there was involvement of the endometrial surface in the form of in situ or early invasive squamous cell carcinoma without myometrial invasion. Case 1 CASE REPORTS A 66yearold Caucasian widow was referred to our institution for definitive surgical therapy for a squamous cell carcinoma of the cervix, Stage 11B. Her medical history revealed an active syphilis and a benign gastric ulcer treated by subtotal gastrectomy six years before. ArgyllRobertson pupils were noted, a VDRL test was positive in a dilution of 1:64, the FTA was 4+, and a spinal fluid serology was negative. Serum carotenes were 21 meqldl (normal: 53 meqldl), vitamin A 138 IU/dl (normal: IUldl), and vitamin C American Cancer Society

No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA * Kanbour and Stock 57 1 FIG. 1. First case. Uterine gross specimen showing the convoluted appearance of the endometrium..3 mg/dl (normal:.22. mg/dl).

endometrial glands. A Wertheim hysterectomy and pelvic node dissection were carried out without complications, and the postoperative course was uneventful. The uterus weighed 7 g.

2 No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA * Kanbour and Stock 57 1 FIG. 1. First case. Uterine gross specimen showing the convoluted appearance of the endometrium..3 mg/dl (normal:.22. mg/dl). A biopsy of an ulcerated cervical lesion revealed an invasive squamous cell carcinoma; a dilatation and curettage unmasked pyometra and squamous cell carcinoma in situ with no normal recognizable endometrial glands. A Wertheim hysterectomy and pelvic node dissection were carried out without complications, and the postoperative course was uneventful. The uterus weighed 7 g. The cervix appeared to be almost entirely replaced by tumor tissue with gross extension into the right parametrium. The endometrial cavity had a distended appearance with thinning of the myometrium which measured.8 cm in thickness at the fundus. The lining of the cavity had a corrugated graywhite appearance (Fig. I). The fallopian tubes appeared normal. The ovaries were atrophic. Histologically, the cervix was almost totally FIG. 2. First case. Endometrial surface replaced with intraepithelial squamous cell carcinoma with intense small cell infiltrate at the base (X86).

3 IA I I Postsurgical death 7 Years 6 Years 5% Years 3 Months 15 years death unrelated 3 years Case Reports in which Squamous Cell Lesions of the Endometrium Were Reported in Association with Squamous Cell Lesions of the Cervix Reference Author Clinical Prognosis and Age Cervical lesion History Endometrium Other involvement stage followup 3 Willis 48 Squamous cell carcinoma Postradiation Entire involvement pyometra Both Fallopian tubes and ovaries 19 Langley and Woodcock 64 Squamous cell carcinoma Not recorded Entire involvement Both Fallopian tubes 1 Baggish and Woodruff? Squamous cell carcinoma Not recorded Entire involvement Both Fallopian tubes 11 Hallgremson 54 Carcinoma in situ Pyometra Entire involvement Both Fallopian tubes 28 Weill 69 Carcinoma in situ Pyometra Entire involvement Left Fallopian tube 25 Quizilibash and Deptrillo 63 Squamous cell carcinoma Not recorded Entire involvement Both Fallopian tubes 6 Carcinoma in situ Not recorded Entire involvement 7 Ferenczy et al. 53 Carcinoma in situ Not recorded Entire involvement 12 HouJensen 58 Carcinoma in situ Pyometra Entire involvement 76 Carcinoma in situ Pyometra Entire involvement 24 Patton 55 Carcinoma in situ with Pyometra Endometrium and microinvasion foci of adenomyosis 27 Salm 67 Carcinoma in situ Pyometra Entire involvement 44 Carcinoma in situ Not recorded Entire involvement 7 Squamous cell carcinoma Not recorded Entire involvement Carcinoma in situ, vaginal cuff 1 Friedell 55 Squamous cell carcinoma Not recorded Entire involvement

4 Clinical Prognosis and Reference Author Age Cervical lesion History Endometrium Other involvement stage followup I1 IIB IIA IIB IB 1 Year 3% Years Died 4 months from disease 11 Years Died 4% Years from disease 4 Years 3% Years 56 Squamous cell carcinoma Not recorded Entire involvement I 3 Years 3 Brocheriou and Pinandeau 63 Squamous cell carcinoma Pyometra Entire involvement 15 Kairyes 57 Squamous cell carcinoma Radiation Entire invdvement pyometra 5 Delattre and Langeron 66 Squamous cell carcinoma Pyometra Entire involvement 4 Cullen 65 Squamous cell carcinoma Not recorded Entire involvement Current series 66 Squamous cell carcinoma Pyometra Entire involvement Fallopian tube 58 Squamous cell carcinoma Pyometra Entire involvement 53 Squamous cell carcinoma Pyometra Entire involvement 6 Squamous cell carcinoma Pyometra Entire involvement 54 Squamous cell carcinoma Pyometra Entire involvement

574 CANCER August 1978 Vol. 42 replaced by an invasive squamous cell carcinoma, nonkeratinizing, large cell type, which extended into the right parametrium.

5 574 CANCER August 1978 Vol. 42 replaced by an invasive squamous cell carcinoma, nonkeratinizing, large cell type, which extended into the right parametrium. The entire endometrial cavity was submitted for examination and was lined by squamous epithelium displaying changes varying from severe dysplasia to carcinoma in situ and carcinoma in situ with microinvasion (Fig. 2). There were no endometrial glands present, but there was an intense mononuclear small cell infiltrate beneath the endometrial lining. The mucosal lining of the intramural and isthmical portions of the right fallopian tube were also replaced completely by neoplastic squamous epithelium with carcinoma in situ (Fig. 3). One of eleven pelvic nodes was found to have metastatic squamous cell carcinoma. The patient received postoperative radiation therapy, but died of recurrent disease four months later. Case 2 A 58yearold gravida 2, para 2, Negro female, three years postmenopausal presented with vaginal bleeding, abdominal pain and an enlarged uterus. A fractional D&C unmasked cervical stenosis and hematometra of approximately 4 cc. The curet tings revealed squamous cell carcinoma with an adenoid pattern. A serology test was positive, and penicillin treatment for syphilis was instituted. A Wertheim hysterectomy was performed one month later with the diagnosis of Stage 11A squamous cell carcinoma of the cervix. The uterus weighed 165 g. There was gross evidence of endocervical obstruction with dilatation of the upper portion of the canal and the endometrial cavity. The endometrial surface was roughened with graywhite patches. There was an indurated endocervical lesion grossly involving the internal os, which, microscopically, was a squamous cell carcinoma, nonkeratinizing large cell type. The tumor infiltrated the endocervical canal and the myometrium of the lower segment of the uterine corpus. The remaining endometrial surface of the fundus was totally replaced with squamous cell carcinoma in situ with intensive small inflammatory cell infiltrate (Fig. 4). This lesion extended into the cornual portions, but did not involve the fallopian tubes. There was no evidence of remaining normal endometrial stroma or glands. The patient is, at present, living and well eleven years after radical surgical therapy. FIG. 3. First case. Intraepithelial squamous cell carcinoma replacing the lining of the right fallopian tube (X 18).

6 No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA. Kanbour and Stock 575 FIG. 4. Second case. Section from the endometrium showing total replacement by intraepithelial squamous cell carcinoma and inflammatory cell infiltrate in the stroma (x253). Case 3 A 53yearold, gravida, para, Caucasian female, two years postmenopausal was referred for surgical treatment of carcinoma of the cervix, Stage 11B, after 18 months of vaginal spotting and bleeding. A radical hysterectomy and pelvic node dissection were performed. A 13 g uterus revealed a gross cervical lesion which, microscopically, was diagnosed as squamous cell carcinoma, nonkeratinizing, large cell type. There was evidence of cervical stenosis and pyometra. The tumor completely infiltrated the cervix and cervical portio, and extended into the endocervical canal as superficial carcinoma in situ covering and penetrating the normal endometrial glands in the lower uterine segment (Fig. 5). Pelvic lymph nodes were negative for metastasis. The patient received postoperative radiation therapy, but died of recurrent disease four and a half years later. Case 4 A 61yearold gravida 5, para 4, abortus 1, Caucasian female, ten years postmenopausal was investigated for an abnormal Papanicolaou smear. Clinically, there was a mild cervical stenosis, but no obstruction or pyometra were evident. There was no contributing medical history. A fractional D&C and a cone biopsy confirmed the diagnosis of an infiltrating squamous cell carcinoma of the cervix, nonkeratinizing, large cell type. A radical vaginal hysterectomy for a clinical diagnosis of cervical carcinoma, Stage IB was performed. The uterus weighed 7 g and revealed cervical stenosis, but not obstruction. Grossly, the tumor appeared to extend upward into the lower uterine segment. Microscopically, the cervical lesion consisted of squamous cell carcinoma infiltrating the cervical stroma and extending up and over the endometrial surface of the lower uterine segment as carcinoma in situ, without involvement of the underlying endometrial stroma and glands (Fig. 6). The patient is alive and well three years postoperatively with no evidence of recurrent disease. Case 5 A 54yearold gravida 7, para 2, one year postmenopausal Caucasian female with a three month history of vaginal bleeding was referred for definitive treatment of squamous cell carcinoma of the cervix, clinical Stage 11A. Her medical history revealed diabetes mellitus which was dietetically controlled, and a benign thyroid nodule. On pelvic examination, the uterus was enlarged, and there was a firm mass occupying the cervix and upper vagina.

7 576 CANCER August 1978 Vol. 42 FIG. 5. Third case. Section from the endometrium showing overgrowth, penetration, and replarement of endometrial glands by intraepithelial squamous cell carcinoma ( x 99). Cervical biopsy revealed invasive squamous cell carcinoma, large cell, nonkeratinizing type. A Wertheim hysterectomy and pelvic lymph node dissection were performed. The uterus, weighing 195 g, showed a circumferential ulcerative lesion occupying the cervix at the external os and extending into the endocervical canal and the lower uterine segment. The endometrial cavity was slightly dilated and filled with foul, necrotic debris. The endometrium was graywhite, polypoidal in appearance. The largest polypoidal structure measured 2. by 1.5 by 1. cm. Microscopically, the cervical lesion consisted of squamous cell carcinoma, large cell, nonkeratinizing, infiltrating the cervical stroma and extending up and over the endometrial surface, including the endometrial polyps, as intraepithelial squamous cell carcinoma. Some of the glands were filled with malignant squamous epithelium without penetration into the myometrium (Figs. 7, 8). In other areas, intraepithelial neoplasm had spread over the endometrium without irivolvement of the endometrial glands. Thirty pelvic lymph nodes were free of tumor. Postoperatively, the patient developed vesicovaginal fistula which was repaired three months after hysterectomy. The patient is alive and well with no evidence of recurrence of cancer two years after radical surgery. DISCUSSION The presence of squamous epithelium occurring in the endometrium has been reviewed extensively by Motyl~ff,~~ Fl~hman,~~~ and Baggish and Woodruff.' Pyometra, nonspecific and specific endometritis, tuberculosis, syphilis, vitamin A deficiency, radiation, foreign bodies including IUD's, chemical agents, exogenous or endogenous estrogens, and intracavity tumors have all been mentioned as associated with or as precursors of this type of lesion. Thus, the presence of squamous epithelium itself within the endometrium is not to be construed as neoplastic or precancerous. However, it may be subjected to those other factors that may lead to malignant changes of squamous epithelium as it occurs in the uterine cervix. Squamous epithelium can be present in association with endometrial adenocarcinoma, as a benign squamous metaplasia (adenoacanthoma) or

No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA. Kanbour and Stock 577 as a malignant component in mixed adenosquamous carcinoma.23 Pure primary squamous carcinoma of the endometrium is extremely rare.

8 No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA. Kanbour and Stock 577 as a malignant component in mixed adenosquamous carcinoma.23 Pure primary squamous carcinoma of the endometrium is extremely rare. Fluhmann' established three criteria for the diagnosis of such lesions. These criteria are 1) no coexisting endometrial adenocarcinoma, 2) no demonstrable connection between the endometrial tumor and the stratified squamous epithelium of the cervix, and 3) no primary cervical carcinoma. In accordance with these criteria, 19 acceptable cases were reported in the world literat~re.'~'~~'~~~~ Th e average age of patients with such a lesion is 61 years. Pyometra was reported in 4% of the cases and the prognosis of such a type of endometrial neoplasm is very poor if compared with other types of epithelial malignancies of the endometri~m.',~~ Another mechanism by which squamous cell carcinoma occurs in the endometrium is through direct extension from cervical squamous cell carcinoma. The common patterns of the uterine corpus involvement by cervical cancer is through deep myometrial penetration and lymphatic dis~emination.'~ Super ficial surface spread of in situ or invasive squamous carcinoma of cervix over the contiguous endometrial surface may occur in rare instances. The intrauterine surface spread of cervical cancer in the endometrium may be evident on gross inspection as whitish patches, a condition called "cake icing" or "Zuckerguss" carcinoma, in which superficial squamous tumor sweeps over or replaces the normal endometrium.6 Such a lesion may involve the entire uterine cavity and extend into the fallopian tubes. In addition to the current five cases of cervical carcinoma with endometrial surface involvement, we found 2 reported cases (Table 1). Of the 25 cases, eight were associated with in situ, one with microinvasive, and 16 with invasive cervical carcinoma. In seven instances, the fallopian tubes were also involved in direct continuity with the cervical and endometrial lesion. In all cases, inflammatory changes were present and pyometra was reported in 14 cases (66%). The mean age of the patients is 6 years, more than ten years above the expected age for cervical cancer. FIG. 6. Fourth case. Section from the endometrium demonstrating glandular and stromal overgrowth of intraepithelial squamous cell carcinoma (X 1).

9 578 CANCER August 1978 Vol. 42

10 No. 2 ENDOMETRIAL SQUAMOUS CELL CARCINOMA. Kanbour and Stock 579 FIG. 7. Fifth case. Section from endometrial polyp showing intraepithelial squamous cell carcinoma of the surface and the endometrial glands. Some of the deeper glands are not involved with the neoplasm (x86). FIG. 8. Fifth case. Section of endometrium showing squamous neoplastic cells, arrow 1, growing under and eventually replacing the normal glandular epithelium of the endometrium, arrow 2 (X2). < Although the data are limited, the survival in treated cases of squamous cell carcinoma of the cervix with contiguous surface spread of the tumor into the endometrium does not appear to be altered and, therefore, does not change clinical staging. This is also true in other forms of uterine involvement with cervical carcinoma, in accordance with the International Federation of Gynecologists and Obstetricians and the American Joint Committee for Cancer Staging.l8 However, Perez et al.,25 in a retrospective analysis of endometrial curettings in patients with cervical carcinoma, reported that in the presence of endometrial stromal invasion by tumor the survival rate is poorer than that of comparable clinical stage of cervical cancer and recommend routine dilatation and curettage for evaluation of cervical carcinoma. Their findings, however, stress the presence of endometrial stroma invasion and not the superficial in situ squamous cell carcinoma of the endometrium. Squamous cell carcinoma in situ in association with cervical carcinoma occurs not only in the endometrium, but also in the vagina as a downward surface extension of the cervical cancer. The latter occurs more frequently. In MageeWomens Hospital Tumor Registry, carcinoma in situ of the vagina is seen in association with cervical cancer at a frequency of 2% while endometrial lesion is at a frequency of.7%.16 The lateral surface growth of malignant epithelium from squamous cell carcinoma occurs through one of two mechanisms. The first, through a process of horizontal spread as postulated by Cullen4 and Ferenczy et al.,7 by which the neoplastic cells mechanically displace and eventually replace the normal glandular epithelium of the endometrium. The second mechanisms is a process of vertical proliferation (Field theory of carcinogenesis) by which transformation of a normal to a malignant cell occurs in a vertical direction, carcinoma in the cervix and in the endometrium arising independently and concurrently by the same cancer stimulating agent.l4,l7 Although the possibility of both mechanisms being operative is conceivable, in most of the reported cases it is apparent that the endometrial lesion is a result of direct extension of the cervical cancer. Histological continuity between cervical, endometrial and fallopian tube lesion is often demonstrated. Cervical stenosis and subsequent pyometra may have a promoting effect for surface propagation of cervical cancer. REFERENCES 1. Baggish, M. S., and Woodruff, J. D.: The occurrence of squamous epithelium in the endometrium. Obstet. Gynecol. Survey 22:69115, Barnett, H.: Squamous cell carcinoma of the body of the uterus.]. Clin. Pathol. 18:715722, Brocheriou, C., and Pinandeau, Y.: A propos d un cas d icthyose uterine propogation. Intraepitheliale d un carcinomr invasif a point de part cervico isthmiqui. Arch. Anat. Pathol. 11:46, , Cullen, T. S.: Cancer of the Uterus. New York, D. Appleton Co., 19; pp Delattre, A,, and Langeron, P.: Stenose carcinoma de listhme uterine avec pyometrere et ichtyose uterine. J. Sci. Med. Bull. 83:62563, Evans, R. W.: Histological Appearance of Tumor. Second Edition. Edinburgh & London, 1966; p Ferencry, A,, Richart, R. M., and Okagaki, T.: Endometrial involvement by cervical carcinoma in situ. Am. J. Obstet. Gynecol. 11:59592, Fluhmann, C. F.: Squamous epithelium in the endo metrium: Benign and malignant condition. Gynecol. Obstet. 46:39316, Fluhmann, C. F.: Comparative studies of squamous metaplasia of the cervix uteri and endometrium. Am. J. Ohstet. Gynrcol. 68: , Friedell, G. H.: Endometrial surface involvement of the uterine cervix. ObstPt. Gynecol. 12:179184, Hallgrimsson, J. T.: Carcinoma in situ of the endocervix, corpus uteri and both oviducts. Acta Obstet. Gynecol. Scand. 46:268272, HouJensen, K.: Simultaneous epidermoid carcinoma in situ of the portiocervix and the endometrium of the uterus. Acta Pathol. Microbiol. Scand. 8: 14, Hopkin, I. D., Harlow, R. A., and Stevens, P. J.: Squamous carcinoma of the body of the uterus. Br.,I. Cancer 24:7176, Johnson, L. D.: The histopathological approach to early cervical neoplasia. Obstet. Gynec. Survey 24:735, Kairys, L. R., Dougherty, C. M., Mickel, A,: Squa

58 CANCER August 1978 Vol. 42 mous cell carcinoma in situ of the endometrial cavity. Am. J. Obstet. Gynecol. 88:548549, 1964. 16. Kanbour, A. I.: Unpublished data. 17. Kay, S.

11 58 CANCER August 1978 Vol. 42 mous cell carcinoma in situ of the endometrial cavity. Am. J. Obstet. Gynecol. 88:548549, Kanbour, A. I.: Unpublished data. 17. Kay, S.: Squamous cell carcinoma of the endometrium. Am. J. Clin. Pathol. 61:264269, Kotmeier, H. L.: Classification and staging of malignant tumor in the female pe1vis.j. Int. Fed. Gynecol. Obstet. 9:172179, Langley, F., and Woodcock, A.: Squamous cell carcinoma of multicentric origin involving cervix, uterus and Fallopian tubes. J. Obstet. Gynecol. Br. Emp. 6 1 : , Malinak, L. R., Miller, G. U., and Armstrong, J. T.: Primary squamous cell carcinoma of the Fallopian tube. Am. J. Obstet. Gynecol. 95: , Levine, S., and Sciorsci, E. F.: Squamous cell carcinoma of the uterine corpus and its relation to pyometra. Cancer 19:485488, Motyloff, L.: Epidermoid heteroplasia of basal cells of endometrium versus squamous cell metaplasia. Am. J. Obstet. Gynecol. 6: , Novak, E. R., and Woodruff, J. D.: Novak Gyne cologic and Obstetric Pathology, Seventh edition. Philadelphia, W. B. Saunders, 1974; pp Patton, W. T., and Squires, G. U.: Icthyosis uteri. Am. J. Obstet. Gynecol. 84: 85886, Perez, C. A,, Zivnuska, F., Askin, F., Kumar, B., Camel, H., and Powers, W. E.: Prognostic significance of endometrial extension from primary carcinoma of the uterine cervix. Cancer 35: , Qizilbash, A,, and Depedrillo, A.: Endometrial and tuba1 involvement by squamous carcinoma of the cervix. Am. J. Clan. Pathol. 64:668671, Salm, R.: Superficial intrauterine spread of intraepithelial cervical carcinma.j. Pathol. 97:719723, Weill, S., Prade, M., and Goldfarb, E.: Epithelioma pavimenteux untraepithelial etendu a tout? la surface de la cavite uterine eta la surface d une trompe. Rapport d un cas. Rev. Fr. Gynecol. Obstet. 63:211214, White, A. J., Buchsbaum, H. J., and Milaglos, A. M.: Primary squamous cell carcinoma of endometrium. Obstet. Gynecol. 41:912919, Willis, R. S.: Pathology of Tumours. London, Butterworths, 1967; p. 539.

A Rare Case of Invasive Squamous Cell Carcinoma of Cervix Extending to Endometrium and Right Fallopian Tube

A Rare Case of Invasive Squamous Cell Carcinoma of Cervix Extending to Endometrium and Right Fallopian Tube Kate Madhuri S 1, Gulhane Sushma R 2, Mane Sheetal V 3 1 Professor and Head, 2 Specialist cum