GYNECOLOGIC ONCOLOGY 21, 124-132 (1985)

Colposcopic Diagnosis of Ovarian Carcinoma Spreading to Cervix: A Case Report

PRITAM SINGH, MRCOG,’ M. PANG, MRCPATH.,” AND S. S. RATNAM, M.D., FRCOG

Department of Obstetrics und Gynaecology:y, National University qf Singapore, Kundang Kerbuu Hospital, Hampshire Road, Singapore 0821; and “Department of Puthology, Nutionul University of Singupore, Singupore General Hospital, Outram Road, Singupore 0316

Received March 29, 1984

Secondary carcinoma of the cervix is uncommon. A patient with a history of ovarian carcinoma had an abnormal cervical smear and colposcopy was performed. Colposcopy and directed biopsy led to the diagnosis of ovarian cancer which had spread to the cervix. The unusual colposcopic features which allowed a clinical diagnosis are correlated with histopathology and the findings discussed. % 1985 Academic Press. Inc.

INTRODUCTION

Primary cervical cancer is one of the most common genital malignancies world- wide. In the United States it now ranks sixth among all cancers in women; cervical cancer is now surpassed in frequency by endometrial and ovarian carcinoma because of a progressive decline in the incidence rate due to the effect of screening by cervical cytology [l]. Cervical cancer is nearly always a primary tumor and predominantly squamous cell type; the other numerous histologic types besides primary squamous and adenocarcinoma varieties are rare [2]. Colposcopy allows the recognition of primary cervical neoplasia in the intraepithelial, preclinical, and clinical invasive stages in the visible part of the cervix; there is good correlation between colposcopic diagnosis and directed biopsy histology [3].

The cervix alone is very rarely the site of secondary metastatic or directly spreading cancer from the stomach [4-Q, breast [7,8], and large bowel [9]. Most reports, however [lo-121, do not make a distinction between lesions involving the corpus, cervix, or both but report extragenital tumors from the breast, stomach, cutaneous melanoma, lung, colon, pancreas, and kidney as producing metastases in the uterus. Reports of cancers metastatic from these organs have been mainly of postmortem material [IO-121 but the diagnosis of cervical involvement has

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CASE REPORTS 125

been rarely made before death [9,13,14]. However, no instances of colposcopic diagnosis of secondary cancer in the cervix could be found in the literature we reviewed. A case of ovarian carcinoma with spread to the cervix which was clinically not apparent until colposcopy was performed to evaluate an abnormal cervical cytological smear is described. The diagnosis of secondary carcinoma in the cervix was made clinically by colposcopy and confirmed by directed biopsy.

CASE REPORT

A 22-year-old Chinese female had a left oophorectomy for a benign-appearing IO-cm diameter unilocular ovarian cyst by a private gynecologist, who noted viscous fluid contents and a smooth inner cyst lining with no solid areas. The opposite ovary, both fallopian tubes, and the rest of the pelvic and abdominal peritoneal cavities were normal; there were no ascites noted. No peritoneal washings or omentectomy were performed. Histopathology reported an invasive mutinous cystadenocarcinoma of the ovary (Fig. 1). Following convalescence she was referred to us for further treatment on the 17th of June, 1981. General physical and pelvic findings were normal apart from the healed surgical incision. Following baseline hematologic and biochemical investigations of renal and hepatic function, intravenous cyclophosphamide 400 mg daily was given for 10 days; this was followed by maintenance with doses of 1400 mg given at 3-week intervals with hematologic monitoring for toxicity. During follow-up, clinical examinations

FIG. 1. Invasive mutinous cystadenocarcinoma in left ovary. ( x 100.)

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and two ultrasound scans of the pelvis in October I98 I and January I982 revealed no detectable abnormality.

On the 24th of February 1982 second-look laparoscopy showed the right ovary, both tubes, the uterus, and the rest of the pelvis to be normal apart from a small volume of fluid in the Pouch of Douglas. The fluid and pelvic peritoneal washings with saline were aspirated for cytologic examination; malignant cells were present in all aspirated samples. The subdiaphragmatic and hepatic surfaces were normal. It was decided to administer c&platinum 50 mg in addition to cyclophosphamide at 3-week intervals. When she was admitted for the .u-st course of the combination therapy on the 6th of April 1982, she complaircd of vaginal discharge and an episode of postcoital bleeding. A pelvic examir &on was done which revealed a clinically normal cervix but no other significant pelvic findings. A cervical smear was taken and reported Class III with severely dyskaryotic cells which were undifferentiated and suggestive of carcinoma-in-situ of the cervix (Fig. 2). She was referred for colposcopy on the 24th of April I:“ 2.

Colposcopy Clinic Findings

Naked-eye examination revealed the cervix to be enlarged and nodular. The ectocervical epithelium appeared normal apart from three tiny 2-3 mm sized, raised dark areas scattered over the anterior lip. Around the cervical OS there was an area which was raised, friable, and appeared to be covered by necrotic slough. Colposcopy showed a normal transformation zone, in the original squamous epithelium of the ectocervix were present the dark raised areas; these had an

FIG. 2. Cervical cytologic smear with undifferentiated cells (Papanicoloau stain). ( x 640.)

CASE REPORTS 127

irregular margin and consisted of dark, shiny, featureless, and smooth-surfaced plaques raised above the ectocervical surface (Fig. 3). The original squamous epithelium in the dark areas was ulcerated but in immediately adjacent epithehum atypical vessels usually associated with invasive cancer could be seen. These vessels had a corkscrew appearance, an irregular calibre, a tortuous course parallel to the ectocervical surface, and extended only 2-3 mm into the epithelium surrounding the ulcerations (Fig. 3, arrow). The rest of the ectocervical squamous epithelium was normal without any abnormal vascular patterns of punctuation or mosaic.

Around the cervical OS there was a raised area with an irregular surface which appeared yellowish due to a layer of necrotic slough but under magnification there were parts which appeared dark and the whole area presented a variegated appearance. In this area there were no abnormal vascular patterns usually associated with a primary squamous or adenocarcinoma of the cervix. The adjacent epithelium of the transformation zone appeared to be benign metaplastic squamous epithelium. Acetic acid (3%) application produced no visible changes in any part of the cervix. The endocervix was examined using Kogan’s endocervical speculum and friable tumor-like tissue present; endocervical curettage produced scanty friable tissue fragments clinically suggestive of tumor.

Multiple biopsies of the ectocervix, the dark raised plaques, the raised slough- covered friable tissue around the OS, and of the endocervix were obtained. A colposcopic diagnosis was made of secondary, directly extending, or metastatic intracervical malignancy probably of the ovarian carcinoma. Secondary tumor

FIG. 3. Colposcopic view of cervix with dark, shiny smooth plaque raised above ectocervical surface. Atypical vessel in adjacent intact squamous epithelium (arrow). (X 16 objective.)

128 SINGH, PANG, AND RATNAM

was also thought to be present around the cervical OS and in the endocervix. Histopathology reported poorly differentiated adenocarcinoma within cervical stroma, the ectocervical epithelium was intact in many parts in biopsies of the ectocervix indicating a lesion pushing outward to the surface from within the cervical substance (Fig. 4). Biopsies from around the OS showed only poorly differentiated adenocarcinoma without covering squamous epithelium as did those from the endocervix (Fig. 5). Histopathologic impression was that the cervical biopsies represented an extension/metastasis from the previously diagnosed ovarian carcinoma.

Further Progress

At laparotomy on the 28th of April 1982, the cervix was enlarged and the uterus bulky, both seemed to be involved by tumor extending from the left lateral pelvic wall into the broad ligament to the uterine isthmus. Tumor infiltration was noted in the vesicouterine area; the right ovary was cystic and enlarged to twice normal size. The subdiaphragmatic spaces and liver were normal; total abdominal hysterectomy and right salpingooophorectomy were performed but macroscopic tumor remained on the left lateral pelvic wall. Histopathology confirmed metastatic poorly differentiated adenocarcinoma in the cervix with extensive infiltration of the myometrium, the endometrium was normal. The right ovary contained extensive intralymphatic and stromal metastatic carcinoma and there was intravascular tumor invasion of the left broad ligament tissues. Fourteen days after operation,

FIG. 4. Colposcopic biopsy showing intact cervical squamous epithelium covering tissue of poorly differentiated adenocarcinoma in the cervical stroma. (x 100.)

CASE REPORTS 129

FIG. 5. Cervical biopsy from the area around the cervical OS showing poorly differentiated ad- enocarcinoma. ( X 100.)

a right pleural effusion developed with straw colored fluid which contained malignant cells. She received one course of triple chemotherapy with &-platinum 67 mg, Adriamycin 67 mg, and cyclophosphamide 1000 mg; 2 weeks later the pleural effusion reaccumulated and she rapidly deteriorated. She died on the 14th of June, 1982; no postmortem was performed.

DISCUSSION

The cervix uteri is a common site of primary carcinoma which is predominantly squamous cell type in about 90% of cases. The other histological types of cervical cancer are adenocarcinomas, mixed carcinomas, carcinoids or “apudomas,” malignant melanomas, and sarcomas which together constitute the remaining 10% [2]. Squamous cell carcinoma and adenocarcinoma are believed to originate from neoplastic change in abnormally transformed epithelium of the transformation zone and columnar epithelium, respectively. Colposcopy can identify intraepithelial and invasive disease in the visible part of the cervix and the colposcopic features are well known and extensively described in works on colposcopy by Kolstad and Stafl [15] and others [16-181.

Secondary carcinoma in the cervix is not mentioned in any of the publications on colposcopy because of its extreme rarity. More comprehensive reports on pathology of cervical carcinomas make a note of metastatic carcinomas [2,19] and Ostergard [20] makes the point that though the cervix is rarely a site for metastatic cancer this occurs sufficiently frequently enough that the possibility

130 SINGH, PANG, AND RATNAM

should be considered in the differential diagnosis. Ostergard [20] also mentions that direct extension of neoplasms from adjacent organs into the cervix is a common clinical finding which may or may not be obvious on either clinical examination or pathological examination of excised tissue. Clinical presentation due to symptoms from secondary cervical cancer alone, however, does not seem to occur to any significant extent and secondary cervical cancer is often found incidently during assessment of the primary tumor [9-l 1,131. Colposopic diagnosis of secondary cancer in the cervix does not appear in the literature we reviewed and standard colposcopy texts [U-18] do not describe or mention the entity at all because of the extreme rarity with which it would seem to present as a problem for colposcopic evaluation of the cervix. Hence, no colposcopic or other features which may make the diagnosis suspect are suggested in the literature to enable recognition of secondary cancer in the cervix.

At colposcopy, the features in this case were clearly not of a primary cervical squamous or adenocarcinoma because of the normal transformation zone and since no foci of intraepithelial or invasive carcinoma of the usual type with the expected abnormal vascular patterns could be seen. The original squamous ep- ithelium of the cervix appeared normal except in areas of focal ulceration; most unusual was the presence of atypical vessels of tumor neovascularization only in the immediately adjacent original squamous epithelium surrounding the ul- cerations, The cervix was bulky, firm, and larger than one would have expected in a nullipara. When the colposcopic features were correlated with the clinical history it was possible to formulate a clinical diagnosis. The presentation fitted well with an intracervical tumor from ovarian carcinoma spreading/metastatic to the cervix and starting to break through to the ectocervical surface at the raised dark areas of ulceration. The presence of atypical vessels in adjacent squamous epithelium which had no other classical colposcopic features of epithelial neoplasia, suggested that it was not a primary cervical cancer. It was apparent that tumor surface was visible at the sites of ulceration and tumor being approximate to the surface squamous epithelium in these parts had somehow induced in the adjacent epithelium neovascularization by vessels like those usually found in invasive cervical cancers. It may be postulated that neovascularization was possibly due to the elaboration of tumor angiogenesis factor. Greenblatt and Shubik [21] suggest that a diffusible angiogenesis factor is released from tumor to nearby endothelial cells and Folkman et al. [22] isolated a tumor angiogenesis factor from human and animal tumors which is mitogenic to endothelial cells and stimulates rapid formation of new capillaries. Greenblatt and Shubik’s [21] studies suggested that the transmission distance of the effect of tumor angiogenesis factor does not exceed 1 mm in width and this fits well with the observation that the neovascularization was confined to immediately adjacent epithelium only. It was at the sites of ulceration that tumor was in closest contact with squamous epithelium and necrotic changes or epithelial slough had not obliterated the observed fine changes of neovascularization. Extensive ulceration of tumor surface, inflammation, and epithelial slough had probably prevented observation of neovascularization in the epithelium adjacent to the area of necrotic tumor around the cervical OS. Furthermore, the area around the cervical OS consisted of visible tumor with a

CASE REPORTS 131

necrotic surface and also possibly because it was not primarily cervical in origin the usual colposcopic features of primary cervical carcinoma were not observed. An alternative explanation maybe that cytotoxic therapy had contributed to necrosis at the visible surface of the tumor which was exposed at the portio in the vagina. Directed biopsy histology confirmed these concepts because biopsies from the squamous-epithelium-covered ectocervix showed poorly differentiated adenocarcinoma in cervical stroma over which the ectocervical epithelium was intact and not infiltrated by tumor. The area around the cervical OS only consisted of poorly differentiated adenocarcinoma without squamous epithelial covering and fragments from the endocervix consisted entirely of tumor tissue.

Colposcopic recognition of intraepithelial, preclinical (occult), and clinically invasive primary cervical carcinoma is routine in colposcopic practice and aids management and planning of therapy. Colposcopy is of great value for identification of residual foci of neoplasia when cytology is positive following apparently adequate treatment of cervical cancer. Cartier [ 161 has described colposcopic identification of subclinical metastases in the vagina following hysterectomy for uterine corpus adenocarcinoma but there appear to be no reports of colposcopic and directed biopsy diagnosis of secondary carcinoma extending/metastatic to cervix. The unique colposcopic features together with the available clinical history allowed a confident colposcopic diagnosis of secondary ovarian carcinoma in the cervix which had clinically not been apparent. An appreciation and understanding of unusual colposcopic features in apparently difficult cases together with a careful review of all available clinical details may allow similar unusual colposcopic diagnoses in the future.

ACKNOWLEDGMENT

We are grateful to Dr. Pauline M. Tan for referring this case.

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