Second Malignancy Following Radiotherapy for Carcinoma of the Cervix: Clear Cell Adenocarcinoma of the Endometrium Infiltrating the Uterus and Ovary

Introduction

Occurrence of second malignancies in long-term cancer survivors poses diagnostic and therapeutic problems. Cancer of the cervix is one of the most common cancers of genital tract, and a variety of second malignancies have been reported following radiation therapy for the treatment of the same. A case of clear cell adenocarcinoma of the uterus occurring 25 years after radiation therapy is reported for its rarity.

Case

A 74-year-old para 6 woman who had been postmenopausal for 25 years, and had a past history of treatment for carcinoma of the cervix, presented with complaints of abdominal pain of 6 months' duration, and an abdominal mass of 20 days' duration. She and her relatives gave a history of surgery followed by radiotherapy, the details of which were not clear. The patient was known to have diabetes and hypertension and was heard of hearing. She had been on antihypertensives and oral hypoglycemic agents for the past 10 years.

On examination, her gait was normal and she weighed 50 kg. She was a febrile and had moderate pallor, and there was no significant lymphadenopathy. Her thyroid was normal. Her breasts were atrophic. There was a localized distension of the abdomen involving the hypogastrium and umbilical region. Palpation of the abdomen revealed thickened and fibrosed skin in the lower abdomen and a 28 week sized mass with variable consistency arising out of the pelvis. There was no ascites. Per speculum examination, the cervix was not visualized. A cystic mass of 28 weeks' size was felt though the vault on vaginal examination. A provisional clinical diagnosis of ovarian tumor was made. Ultrasound of the abdomen showed a 15×12 cm mass in the lower abdomen with echogenic/solid areas within the mass. The uterus was not seen. The mass was between the rectum and the bladder. Contrast-enhanced computed tomography (CECT) revealed a 15×18×12 cm cystic lesion with solid components in the retrovesical pouch on right side of the vault, possibly arising from the right ovary with focal loss of fat planes with distal ileal loops over it. No significant lymph nodes were noted in the abdomen. The liver had multiple small hepatic cysts of 1.5 cm. Vertebral bodies showed osteoporosis. Serum CA-125 was 0.9 milli-international units (mIU), and liver function tests, renal function tests, and serum electrolytes were within normal limits. HIV and hepatitis B surface antigen (HBsAg) were negative. Upper gastrointestinal (GI) endoscopy was normal. Electrocardiogram (ECG) showed a left bundle branch block and echocardiogram was normal. Chest radiograph revealed mild cardiomegaly. Ophthalmology evaluation revealed bilateral cataracts and early nonproliferative diabetic retinopathy. Hemoglobin (Hb) was 10 gm%, bleeding time was 1 min and 30 s, clotting time was 3 min and 30 s, prothrombin time was 17.1 (control 14.4), and international normalized ratio (INR) was 1.21.

Elective laparotomy revealed the mass to be uterine with omental adhesions and ileal loops adherent to its anterior surface. As it was cystic, decompression was performed by inserting an 18 gauze needle at the fundus and connecting it to the suction cannula. After partial decompression, the uterine wall was found to be thickened, the left ovary appeared normal, and the right ovary was enlarged to 5×4 cm and was densly adherent to the uterine wall. Both tubes appeared normal but thickened. The decompressed fluid was hemorrhagic pus. The patient was kept in the lithotomy position and the cervix was explored vaginally. There were no cervical lips and there was a blackish dimple in the center of the vault high up. An attempt was made to pass the uterine sound though this with the idea of draining the pyometra completely after dilatation. This was not possible, however, as the bladder was closely adherent to the anterior vaginal wall and vault. As the size of the uterus was ∼16 weeks, and it was felt to have some solid mass inside, the fundus was opened by a 2 cm vertical incision and the cavity was inspected. There was a fleshy growth in the cavity extending lower down to the isthmus. The incision was sutured back and subtotal hysterectomy with bilateral salpingo-oopherectomy was performed. The cervix was much thinned out and adherent to the bladder, and tissues were friable. There were no palpable pelvic or para-aortic lymph nodes. The liver, gallbladder, and stomach felt normal to palpation. Saline wash was given and the abdomen was closed after inserting an intraperitoneal drain. One unit of blood was transfused intraoperatively. The patient received ceftriaxone and metronidazole for 7 days. Pus culture grew nonfermenting gram-negative bacilli sensitive to ampicillin, gentamicin, and ciprofloxacin. She was treated with ciprofloxacin. There were no significant postoperative complications.

The histopathology report was as follows. The gross description was of a specimen of uterus with bilateral adnexa measuring 9×8.5×1.5 cm. The cervical end was dilated and filled with necrotic friable material with exudate covering it. The cervical lips were not distinctly identifiable. Left tubal segment measured 5 cm and lumen was seen on cut section. The left ovary was 1.5×0.8×0.2 cm. The right tube was 6 cm in length and was adherent to the lateral wall of the uterus. The right ovary measured 4×2.5×1 cm. The outer surface had no capsular breach and showed congested blood vessels. The cut section had gray-white lobulated areas replacing the entire parenchyma. The gray-white areas were soft to firm in consistency and adherent to the uterus.

The cut section of the uterus and isthmus and uterine cavity were completely replaced by the tumor, which was reaching up to the serosa. The tumor was gray-white to yellow with friable areas, with the fundal portion showing dense hemorrhage.

Microscopic picture showed clear cell carcinoma of the endometrium infiltrating the wall of the uterus. The tumor extended to the isthmus and lower segment of resection. Extensive areas of necrosis and calcification were noted. The tumour was infiltrating the right ovary and totally replacing the ovarian stroma. The right tube, left ovary, and left tube were free of tumor.

Discussion

Second malignancies reported following treatment for carcinoma of the cervix may occur in the genital tract and the neighboring organs, such as the bladder and rectum, and in distant organs such as the lungs, bone, and liver. Radiation exposure was proposed to be one of the risk factors for development of second malignancies. A large series that compared the incidence of second cancers following radiation therapy and without radiation therapy for cancer of the cervix found the relative risk to be 1.1 for development of cancers close to the organs of irradiation. The risk was found to be increased with increasing time since treatment. It was also found that women who were <30 or >50 years of age were at greatest absolute risk for developing a second cancer when irradiated. ¹ A retrospective analysis of 46 second cancers of the lower genital tract reported the mean age of patients at the time of diagnosis of the second cancer to be 63 years, and the median time for their diagnosis or discovery to be 206 months. ² Estimating the risk of all second cancers among 104,760 one year survivors of cervical cancer, it was found that the overall risk was increased significantly. And it was increased further when compared with those who did not receive radiation. Cervical cancer survivors treated by radiation were at a statistically significantly increased risk in each latency interval for second cancer at any site, and the risk for second cancers at heavily irradiated sites increased. The increased risk persisted for >40 years.^3. Although a few studies did not find any difference in risk of second cancer relating to the dose of irradiation, ¹ Hall and colleagues reported intensity-modulated radiation therapy (IMRT) to have caused the incidence to double. ⁴

Behtash and colleagues reported uterine papillary serous carcinoma that occurred 16 years after pelvic radiation for invasive carcinoma of the cervix. ⁵ Eight cases of endometrial cancer that developed after radiation therapy for carcinoma of the cervix were evaluated by Gallion and colleagues. Of the 8 uterine cancers, 3 were papillary serous cancers. ⁶ The present case showed clear cell adenocarcinoma, which is rare, and usually arises in atrophic endometrium. It accounts for 1%–6% of all endometrial cancers, and has aggressive behavior and poor prognosis. The etiology is not well understood, but one recent study identified putative precursor lesions in 90% of uterine specimens from women with endometrial clear cell cancer. These lesions were typically isolated glands or surface epithelium within an otherwise normal endometrial region that displayed cytoplasmic clarity and/or eosinophilia with varying degrees of nuclear atypia. ⁷ The genetic expression of clear cell carcinoma is different from that of endometrioid and papillary serous histologic types, and it showed a remarkable similarity of gene expression pattern across the three organ sites, that is, endometrium, ovary, and kidney. Clear cell cancers are more common in older women, among tamoxifen-treated breast cancer patients, and in women diagnosed with endometrial cancer following pelvic radiation for another condition.^8,9. Endometrial carcinomas in the elderly were less likely to be estrogen related, more aggressive, histologically less differentiated, and often nonendometrioid, compared with the general population. ⁸

Two cases of secondary malignant hystiocytoma of the right gluteal muscle were reported by Ohno and colleagues, which resulted in poor outcome. ¹⁰ The prognosis of the second cancers is poor, and the treatment depends upon the site and the extent of spread. In the 46 cases of second cancers of squamous cell carcinomas involving the genital tract, the treatment consisted of surgery in 12 patients (26%), radiotherapy in 23 (50%), combined surgery and radiotherapy in 5 (11%), chemotherapy in 4 (9%), and surgery plus chemotherapy in 1. Median survival was 52 months and 5 year survival from the diagnosis of second malignancy was 47.5%. No prognostic factors for survival were identified. ²

Misdiagnosis of second malignancies may occur, as happened in the case of postirradiation bladder cancer reported by Nimmanon and Ruengpoka, in which malignant fibrous hystiocytoma of the urinary bladder that occurred 15 years after radiation therapy for cervical cancer, was misdiagnosed initially as high grade urothelial carcinoma. ¹¹ Endometrial cancers are usually diagnosed by performing endometrial biopsy or fractional curettage for postmenopausal bleeding. Misdaignosis occurred in this case because of the history of surgery followed by radiotherapy for carcinoma of the cervix 25 years previously, and the fact that clinically the cervix was not seen or felt. Radiologically, misdiagnosis also occurred, as the uterine wall was very thinned out and the contents appeared to be partly anechoeic and partly echogenic and continuous with the wall of the uterus, which was mistaken for the cyst wall. The risk factors for development of endometrial carcinoma in the present case were radiation to the pelvis, diabetes, hypertension, and, possibly, chronic inflammation of the endometrium and age.

Conclusions

Misdiagnosis of uterine malignancy as ovarian tumor can happen in elderly women with a previous history of pelvic irradiation. Complete/partial destruction of the cervix following radiotherapy can cause retention of uterine secretions and chronic inflammation. This may be an additional reason for the development of endometrial malignancy in post-irradiated patients with cancer of the cervix. Secondary malignancy should be one of the differential diagnoses when a mass lesion is detected in the pelvis in elderly women with a past history of malignancies.