Background

Urothelial carcinoma (previously transitional cell carcinoma) of the bladder is the ninth most common cancer and usually presents between the ages of 50 and 60 years in adult patients [1]. Risk factors for this cancer include cigarette smoking, occupational carcinogen exposure, excessive chlorine exposure, chronic cystitis, human papilloma virus (HPV) infection, poor fluid intake, certain medications, high arsenic load, hereditary cancer syndromes, and aristolochic acid use [1]. Presenting symptoms include hematuria, irritative symptoms, or obstructive voiding. Diagnosis is typically achieved by urine cytology with cystoscopic biopsy. Case report data suggest that serum β-human chorionic gonadotropin (HCG) can be produced by urothelial carcinoma [1,2,3]. Despite this known phenomenon, diagnosis of urothelial carcinoma by HCG elevation is rare, and persistently elevated HCG levels may warrant not only a gynecologic, but also urologic work-up.

Case

The following is a case of persistently elevated β-HCG levels five months after vacuum-assisted aspiration of an incomplete abortion. A 49-year-old non-Hispanic, Caucasian woman, gravida 1 para 0, with polycystic ovarian syndrome marked by irregular periods, former smoking history, high-risk HPV infection, and hypertension, presented to the emergency department with heavy vaginal bleeding and passage of fetal tissue in the setting of newly diagnosed pregnancy. On admission to the emergency department, she was normothermic and normotensive with a normal heart rate. Her physical examination revealed significant vaginal bleeding, and bedside ultrasonography revealed a slightly heterogeneous endometrial lining. Manual vacuum aspiration was completed at the bedside for incomplete abortion. Analysis of her urine showed significant hemoglobin, which was attributed to her vaginal bleeding. Surgical pathology confirmed 12.5-grams fetal tissue and 20-grams placenta, consistent with 11-week gestational age. On admission to the emergency department, HCG level was 1800 mU/mL, which trended downward to 12.5 mU/mL within 17 days (Table 1). Additional HCG level was not pursued to establish a return to normal HCG level due to regular menses and patient adherence to follow-up. Two months after her initial emergency department presentation, she saw Obstetrics and Gynecology (OB-GYN) to complete routine Pap testing, which showed no epithelial abnormality, but she tested positive for other high-risk HPV subtypes, and was planned to follow routine cervical cancer screening guidelines.

Table 1 HCG trend through the clinical course
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Five months after her vacuum-assisted aspiration, the patient was scheduled to complete orthopedic surgery. However, her urine HCG testing was positive on the day of surgery. Patient was asymptomatic, and the quantitative HCG level was 23.6 mU/mL on the day of surgery. Patient was referred to OB-GYN for management of HCG findings. One week later, repeat HCG testing showed an HCG quantitative level of 20.8 mU/mL, and nine days after her planned orthopedic surgery date, HCG quantitative level was 24.5 mU/mL, and HCG qualitative urine testing was still positive. To rule out pituitary HCG production, follicle-stimulating hormone (FSH) levels and luteinizing hormone (LH) levels were drawn and found to be normal.

One month after diagnosis of persistent HCG levels, saline-infusion sonography was completed due to concern of possible retained products of conception. It showed two discrete calcifications in the endometrium, and hysteroscopic evaluation was recommended. At her preoperative evaluation for her planned hysteroscopy, she complained of urinary odor for which another analysis of her urine was sent, showing hemoglobin (Table 2). Therefore, the patient requested referral to urology. Hysteroscopy with dilation and curettage, and hysteroscopic myomectomy was completed. Surgical pathology showed benign fibroid with no evidence of retained products of conception or neoplastic tissue.

Table 2 Findings on urine analysis during clinical course
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Despite her hysteroscopic procedure, post-procedure serum HCG quantitative level was 22.6 mU/mL one week later. Therefore, a decision was made to complete methotrexate therapy for concern for possible ectopic pregnancy. One week after methotrexate therapy, HCG level was still 24 mU/mL. Therefore, Gynecology Oncology was consulted, and the patient was recommended to complete a more sensitive test for β-HCG, named “beta sub-unit HCG tumor marker.” Now, two months after her orthopedic surgery date, this highly sensitive β-HCG quantitative tumor marker level was again elevated at 27 mU/mL.

Owing to her request, the patient saw Urology for hematuria, who recommended computerized tomography (CT) urogram, which was significant for microlobulated enhancing bladder mass within superior anterior urinary bladder with some punctate faint wall calcifications. Urology recommended cystoscopy and transurethral bladder tumor resection, and Gynecology Oncology recommended repeat β-HCG tumor marker level in three weeks, oral contraception for ovarian suppression, and follow-up on bladder surgical pathology. Surgical pathology from her cystoscopic resection was consistent with high-grade papillary urothelial carcinoma with invasion into the lamina propria. Macroscopically, the specimen was described as irregular fragments of soft tan-brown tissue that measure 3.5 × 1.9 × 0.3 cm with an aggregate weight of 1.0 grams. Post-procedure β-HCG quantitative tumor marker level was 5 mU/mL and, one month after tumor removal, β-HCG quantitative tumor marker level < 1 mU/mL. The patient completed urologic restaging and completed immunotherapy instillations with Bacillus Calmette–Guérin (BCG) with two rounds of induction; however, she was noted to have persistent urothelial carcinoma in situ and severe dysplasia on two subsequent post-BCG treatment cystoscopic biopsies four months and seven months after initiation of BCG. Therefore, given high risk of recurrence, she underwent complete anterior pelvic exenteration with ileal conduit one year after diagnosis of persistently elevated HCG levels. She currently has no evidence of disease.

Conclusion

Persistently elevated HCG levels require diagnostic evaluation with careful consideration of the following etiologies, including ectopic pregnancy, endocrinopathy, retained products of conception after uterine evacuation, and neoplastic etiologies. Any elevation of HCG without documented intrauterine pregnancy should be considered pathologic and be investigated as such. As in this case, a thorough evaluation of the hypothalamic-pituitary axis, uterine cavity, and urinary system should be completed. Particularly, when considering neoplastic work-up, both gynecologic and urologic carcinomas should be considered. More commonly, β-HCG elevations are related to gynecologic malignancies, such as trophoblastic disorders, and ovarian neoplasms. However, case report data suggest that β-HCG elevation can be found in urothelial carcinoma.

Although urothelial carcinoma is a common bladder malignancy, diagnosis is rarely elucidated with β-HCG elevation, which is a limitation of the application of this finding for diagnosis of urothelial carcinoma in other populations. Use of tissue, serum, or urine biomarkers for diagnosis of urothelial carcinoma is controversial as it is characterized as a heterogeneous disease without one set of distinct tumor markers [4]. Currently, biomarkers, such as nuclear matrix protein 22, bladder tumor antigen (BTA), and BTA tak, ImmunoCyt, UBC test, Cyfra 21-1, and Cxbladder monitor, have been studied for diagnosis [4]. Notably, β-HCG is not a routine or recommended screening biomarker for urothelial cancer. In this case, HCG was also not used as a marker of monitoring treatment, which is another limitation to the use of HCG in the setting of urothelial carcinoma. Instead, surveillance through cystoscopic bladder biopsies is recommended for treatment monitoring after diagnosis. However, this patient demonstrated multiple risk factors for urothelial carcinoma, including high-risk HPV-positive status, former smoking, and hematuria, warranting further urologic evaluation. On discussion with the patient on her perspective, she is grateful for the dedicated gynecologic and urologic care and recommends advocating for abnormal urine analysis results, as she demonstrated when she requested urologic consultation, which led to her final diagnosis.