Lisa B E Shields, Arash Rezazadeh Kalebasty

Abstract

Key words: Oncology; Clear cell adenocarcinoma; Urethra; Chemotherapy; Personalized;Genetic testing; Case report

INTRODUCTION

Clear cell carcinoma of the urethra represents less than 0.02% of all malignancies in women with an annual age-adjusted incidence rate of 1.5 per million females in the United States[1]. Adenocarcinomas account for 10% of female urethral carcinomas, of which 40% are the clear cell variant[2-4]. The majority of cases occur in postmenopausal women, with a mean age of 58 years[5]. Presenting symptoms often include dyspareunia, dysuria, hematuria, pelvic pain, and urinary obstruction, urgency,frequency, and incontinence[1,6-8].

Clear cell adenocarcinoma of the urethra is thought to arise from surface urothelial metaplasia, mesonephric (Wolffian), or Müllerian rests[4,5,7]. It is often located proximally in the urethra with a tendency to metastasize and is associated with urethral diverticulum[3-9]. The most significant prognostic factors include pathological stage and tumor location, with proximal tumors having a worse prognosis[4,10]. A diagnostic urethrocystoscopy and biopsy are usually performed to confirm the diagnosis of clear cell carcinoma of the urethra which are frequently followed by more extensive surgical intervention[5,7]. Pelvic radiation is occasionally considered when there is lymph node involvement, whereas chemotherapy has shown to be of minimal benefit[5]. Genetic testing for personalized and targeted cancer therapy detects mutations in the DNA of cancer cells[11]. Determining the presence or absence of certain mutations may predict whether a patient with cancer may benefit from a particular chemotherapy regimen.

We report the successful use of non-platinum-based chemotherapy in clear cell adenocarcinoma of the urethra. The distinctive characteristics, differential diagnosis,and management of clear cell adenocarcinoma of the urethra are discussed.

CASE PRESENTATION

Chief complaints

A 40-year-old woman presented with a 3-year history of slow urinary flow and a 3-mo history of urinary urgency and frequency as well as gross hematuria.

History of present illness

She denied fever, chills, nausea, vomiting, and flank pain.

History of past illness

The patient had a 3-year history of slow urinary flow and a 3-mo history of urinary urgency and frequency as well as gross hematuria.

Personal history

Past medical history was significant for diabetes mellitus, hypertension,hyperlipidemia, sleep apnea, chronic obstructive pulmonary disease, shingles, and hypothyroidism.

Physical examination upon admission

Height: 5’ 5.5” (1.66 m); Weight: 287 lbs (130.2 kg); Body Mass Index: 47.03 kg/m2.Physical examination detected one cyst-like lesion measuring approximately 1.0 cm in the distal urethra.

Imaging examinations

An abdominal and pelvic computed tomography scan with IV contrast demonstrated multiple bladder calculi, enlarged lymph nodes in the abdomen and pelvis with the largest in the right inguinal area measuring 2.2 cm, and a rounded mass measuring 4.0 cm arising from the left adrenal. Cystoscopy revealed multiple bladder calculi and inflammatory tissue throughout the course of the urethra. The former, with a total stone volume less than 2.5 cm, were extracted. The actively bleeding tissue emanating from the urethral meatus was excised. The diagnosis of the tumor arising from the urethra was based on cystoscopic findings revealing that the tumor was in the urethra and not in the bladder and bladder neck.

Histological analysis demonstrated a proliferation of cuboidal cells lining tubulopapillary structures that merged with the squamous mucosa of the urethra(Figure 1A and B). While some cells were relatively uniform with round nuclei and others exhibited nuclear pleomorphism, rare cells showed marked nuclear enlargement. The cytoplasm varied from eosinophilic to vacuolated to focally clear(Figure 1A and B). Immunohistochemical and histochemical stains were positive for periodic acid-Schiff (Figure 1C), cytokeratin (CK) AE1/AE3, CK7 (Figure 1D), PAX8,and CD15 and negative for mucicarmine, CK20, p63, and CK 5/6. The Ki-67 proliferative index was 25%-30% overall but as high as 50%-60% in some areas. The patient was diagnosed with clear cell adenocarcinoma of the urethra. A positron emission tomography (PET) scan revealed multiple enlarged hypermetabolic lymph nodes throughout her body, a 4.0 cm × 3.7 cm hot soft tissue density mass near the proximal urethra, and a 4.3 cm soft tissue left adrenal mass (Figure 2A). An ultrasound guided fine-needle aspiration biopsy of a left inguinal lymph node was performed.

FINAL DIAGNOSIS

A metastatic poorly differentiated adenocarcinoma revealing stage IV disease was microscopically confirmed.

TREATMENT

The patient underwent suprapubic catheter placement with ongoing dysuria and hematuria. She was seen in medical oncology consultation, and limitations for offering systemic treatments were discussed. A tumor sample was submitted for specialized testing (BiospecifxR, Precision Therapeutics, Inc., Eagen, MN, United States) to determine personalized chemotherapy. The process to determine the individualized chemotherapy took one month to complete. The findings revealed a positive angiogenesis pathway for the expression of vascular endothelial growth factor[12,13], ERCC1[14-16], BRCA1[16-19], and Topo2α[20-22]. ERCCA positivity excluded platinum-based therapy, while BRCA1 positivity was the rationale for taxane-based therapy. Vascular endothelial growth factor positivity indicated the use of bevacizumab.

After 3 cycles of paclitaxel and bevacizumab, a PET scan showed a definite improvement in size and metabolic activity in mediastinal, right iliac, obturator, and bilateral inguinal adenopathy (Figure 2B). The patient achieved radiographic complete response on restaging PET scan after 6 cycles of therapy (Figure 2C).Bilateral lower extremity edema was the only complication which delayed one cycle of combination therapy. The patient concluded a total of 11 cycles of paclitaxel and bevacizumab, reflecting a progression-free survival of 12 mo. A PET scan subsequently confirmed multiple areas of metastatic disease, including the mediastinum, arch of C1, liver, and spleen.

The patient was treated with two cycles of doxorubicin as the specialized testing revealed Topo2α positivity. A PET scan subsequently demonstrated a mixed response to the doxorubicin with some lymph nodes appearing less glucose avid and others having increased metabolic activity as well as a moderate amount of ascites in the abdomen and pelvis, most likely due to peritoneal carcinomatosis. The patient underwent a paracentesis, with aspiration of 4500 mL of fluid.

Figure 1 Histopathological examination. A: Histological examination of clear cell adenoma of the urethra demonstrating the tubulopapillary growth pattern of the tumor (Hematoxylin-eosin staining, 200 ×); B: Higher magnification view of (A), with a better view of the clear cytoplasm and cytologic details (Hematoxylin-eosin staining,400 ×); C: Tumor cells with intracytoplasmic periodic acid-schiff-positive material, consistent with glycogen (periodic acid-schiff stain, 400 ×); D: Tumor cells are diffusely positive for the epithelial marker cytokeratin 7 (Cytokeratin 7Immunohistochemistry stain, 400 ×).

OUTCOME AND FOLLOW-UP

The patient developed complications from pseudomonas urinary tract infection likely from a suprapubic tube and was hospitalized. She died two weeks later, indicating a 14-mo overall survival.

DISCUSSION

A comprehensive examination of the differential diagnosis is imperative to accurately diagnosis and treat clear cell carcinoma of the urethra. The histology of clear cell carcinoma of the urethra is marked by tubule-cystic, papillary, and solid patterns,while the cytology often displays clear cytoplasm, hobnail cells, flat to cuboidal morphology, nuclear pleomorphism, tumor necrosis, and mitotic activity[1,5-9]. In addition, the immunohistochemical staining is often positive for PAX1, PAX8, CK 7,cytokeratin AE1/AE3, and p53 with an elevated Ki-67 (greater than 25%)[1,4,5].Nephrogenic adenoma closely mimics clear cell carcinoma of the urethra with the triad of tubulocystic, papillary, and solid growth pattern although does not possess mitotic activity and there is no infiltrative or prominent solid growth pattern[1,5,9].Additionally, nephrogenic adenoma does not have an increased Ki-67 proliferative index, a positive p53, and does not give rise to clear cell carcinoma of the urethra.Metastatic clear cell carcinoma of the female genital tract and metastatic clear cell renal cell carcinoma should also be excluded[4,6,8].

Figure 2 Positron emission tomography scan. A: Prior to non-platinum-based chemotherapy consisting of paclitaxel/bevacizumab; B: Following 3 cycles of this combination chemotherapy; C: After 6 cycles of this combination chemotherapy.

Appropriate imaging used in the diagnosis of clear cell adenocarcinoma of the urethra includes ultrasound, computed tomography scan, isotope bone scan, and magnetic resonance imaging, with the latter demonstrating preservation of the intratumor urethra, a small tumor height-to-width ratio, as well as a urethral diverticulum and intratumoral septa[3,5]. In our case, FDG-PET results correlated with clinical and tumor response by evaluating the size and activity of metastatic sites.Following diagnostic urethrocystoscopy and biopsy with confirmation of clear cell adenocarcinoma of the urethra, a dilemma exists regarding the extent of surgical resection. In 2013, the European Association of Urology assigned a grade B recommendation for primary urethral carcinoma to use urethra-sparing surgery for anterior urethral cancers, if negative surgical margins could be achieved[23]. However,a more radical surgery such as anterior pelvic exenteration in women and cystoprostatectomy in men may be required due to the aggressive nature of this tumor and the likelihood of recurrence[1,5-7]. Consolidation radiotherapy to the pelvis has been utilized in the treatment of clear cell adenocarcinoma of the urethra when the pelvic lymph nodes are involved[5].

Chemotherapy has been described in the management of urethral carcinoma[24-26],however, a paucity of studies has reported its use in the clear cell variant[7,27]. G?gus and colleagues reported the case of a man with clear cell adenocarcinoma of the urethra who underwent a radical cystoprostatectomy with bilateral inguinal and pelvic lymph node dissection and urethrectomy[27]. Para-aortic lymphadenopathy was noted five months after this surgery which demonstrated tumor metastases on abdominal computed tomography and fine-needle aspiration. He subsequently underwent three cycles of methotrexate-vinblastine-epirubicin-cisplatin chemotherapy but then showed progression and died 10 mo after his surgery.Liedberg and colleagues reported four cases of clear cell adenocarcinoma of the female urethra, two of whom were treated with chemotherapy[7]. After undergoing a cystourethrectomy, one of these patients was treated with adjuvant local radiotherapy and concomitant weekly cisplatin. No evidence of disease was observed at 6-mo follow-up. The other patient underwent an anterior exenteration following which she did not have adjuvant therapy. However, she experienced a locoregional recurrence after 12 mo and received an unspecified chemotherapy. These authors did not provide the chemotherapy outcome. In Dayyaniet al[26]study of 44 patients with squamous cell carcinoma and adenocarcinoma of the urethra, the overall response (complete and partial) rate to platinum-containing neoadjuvant chemotherapy was 72%. This finding suggests that preoperative chemotherapy is associated with prolonged disease-free survival in a subgroup of lymph node positive cases.

Herein, we report the first case in the literature of a patient with clear cell adenocarcinoma of the urethra who underwent personalized chemotherapy testing and was treated successfully with a non-platinum-based chemotherapy. Following 3 cycles of paclitaxel/bevacizumab she attained complete clinical remission, and a PET scan showed a definite improvement in size and metabolic activity in mediastinal,right iliac, obturator, and bilateral inguinal adenopathy. The patient concluded 11 cycles of paclitaxel/bevacizumab, representing a progression-free survival of 12 mo.Lymphedema of the lower extremities was the sole complication.

CONCLUSION

Individualized medicine through personalized chemotherapy testing offers a unique clinical and therapeutic approach to managing the exceedingly rare clear cell adenoma of the urethra. Our case demonstrates the efficacy of non-platinum-based chemotherapy in the treatment of clear cell adenoma of the urethra. Due to the scarcity of this tumor type, it is difficult to conduct larger studies to establish the safety and efficacy of non-platinum-based chemotherapy. Assessment of the gene alterations in cancer cells can be helpful in selecting systemic treatment for this rare cancer.