Long‐term disease control after upfront chemotherapy and surgery in a patient with primary prostate leiomyosarcoma

Introduction Prostate leiomyosarcoma is a rare, aggressive neoplasm. Case Presentation A 52‐year‐old man presented with worsening frequent micturition and painful urination. Rectal examination revealed a significantly enlarged prostate. Magnetic resonance imaging showed a large prostate tumor with urinary bladder and bilateral seminal vesicle invasion. A prostate biopsy revealed diffuse proliferation of pleomorphic atypical cells. Immunohistochemistry confirmed the diagnosis of prostrate leiomyosarcoma. The patient received three cycles of the mesna, doxorubicin, ifosfamide, and dacarbazine regime (mesna 6000 mg/m2, doxorubicin 60 mg/m2, ifosfamide 7500 mg/m2, and dacarbazine 900 mg/m2) at 4‐week intervals. The tumor shrank by 28% and exhibited necrotic changes. He underwent total pelvic exenteration with en bloc resection of the prostate, bladder, rectum, and anus. Pathological surgical margin was negative. The patient is alive with no disease at 5 years postoperatively. Conclusion Neoadjuvant chemotherapy and surgical resection are essential to achieve a long‐term survival of patients with localized prostate leiomyosarcoma.


Introduction
Sarcomas of the prostate are rare and account for 0.1-0.2% of all malignant prostatic tumors. Rhabdomyosarcomas of prostate are known as the most frequent tumors in childhood, whereas leiomyosarcomas are the most common sarcomas involving the prostate in adults. 1 Prostate sarcomas have conventionally been treated with radical surgery including prostatectomy, cystoprostatectomy, and total pelvic exenteration. The prognosis of prostate sarcomas has been poor with surgery alone. We report the case of a patient with prostate leiomyosarcoma treated with total pelvic exenteration after neoadjuvant chemotherapy.

Case report
A 52-year-old man presented with a complaint of frequency and difficulty in urination since February 2016. The patient visited a urologic clinic and received antibiotics and an a1blocking agent. However, the perineal pain and difficulty in urination worsened. The patient was referred to our hospital in May 2016. Rectal examination revealed a significant enlargement of the prostate with unclear margins. The prostate specific antigen level was 0.8 ng/mL. MRI (T2 weighted image) showed a heterogeneous, large, prostate tumor (10.6 9 9.3 cm) with invasion into the urinary bladder and bilateral seminal vesicles without invasion of the rectal wall or internal obturator muscle, as shown in Figure 1. CT demonstrated right hydronephrosis due to tumor compression but no metastasis to lymph nodes or visceral organs. A transrectal ultrasoundguided prostate biopsy was performed and the results are shown in Figure 2. H&E-stained sections revealed diffuse proliferation of pleomorphic atypical cells with chromatinrich small nuclei. Leiomyosarcoma of the prostate was confirmed via immunohistochemical staining; tumor cells were positive for a-SMA, desmin, and vimentin and negative for androgen receptor, NKK3.1.
After consulting the oncologist at our hospital, we decided to apply preoperative chemotherapy with MAID regime. The patient underwent three cycles of MAID regime comprising mesna 6000 mg/m 2 , doxorubicin 60 mg/m 2 , ifosfamide 7500 mg/m 2 , and dacarbazine 900 mg/m 2 , every 4 weeks from June 2016. Grade 3 febrile neutropenia was observed after every cycle, despite subcutaneous pegfilgrastim injections. CT after three cycles of chemotherapy showed 28% tumor shrinkage and obvious necrotic changes in the tumor, as shown in Figure 3. Finally, total pelvic exenteration was performed, wherein the prostate, bladder, rectum, and anus were en bloc resected and replaced with an ileal conduit and sigmoid colostomy in September 2016. The surgical pathology is shown in Figure 4. The H&Estained sections revealed that nearly all of the tumor cells were necrotic and only those invading the muscle layer of the urinary bladder were viable. The surgical margins were microscopically negative. The patient received no adjuvant chemotherapy and is alive with no disease at 5 years postoperatively.

Discussion
LMSOP is very rare, and <200 cases have been reported to date. 2 Most common symptoms of LMSOP are urinary obstruction and urinary frequency, such as urgency, and nocturia. As the tumor grows, hematuria, perineal and/or rectal pain, constipation, burning on ejaculation and weight loss are observed. LMSOP presents as nonspecific enlargement of the prostate upon physical examination and diagnostic imaging. Serum PSA levels are not almost higher than within normal limits; therefore, most patients are diagnosed by using ultrasoundguided needle biopsy. 3 Microscopic findings of LMSOP are characterized by high-grade hypercellular lesions comprising eosinophilic spindle-shaped cells with mitotic changes, prominent necrotic lesions, and cystic degeneration. Vimentin, SMA, and desmin are commonly expressed in neoplastic cells and cytokeratin in approximately 25% of the cases. 3 Clinical outcomes for patients with LMSOP are poor. A review of 34 patients with LMSOP demonstrated that median survival is 17 months (95% CI 20.7-43.7 months) and the survival rates at 1,3,5 years are 68%, 34%, and 26%, respectively. The OS of patients with metastasis at initial diagnosis was worse than that of those with no metastasis (median OS, 5 vs 20 months, P = 0.018). The OS of patients with incomplete resection was worse than that of those showing negative surgical margin (median OS, 13 vs 41 months, P = 0.008). 3 For patients with localized disease, complete resection with negative surgical margin is the optimal treatment and represents the possibility of curing disease. However, Wang et al. reported there was no significant correlation between the status of surgical margin and OS. 4 Sexton et al. 5 and Musser et al. 6 reported their experiences with prostate sarcoma in 21 (12 with LMSOP) and 38 patients (13 with LMSOP), respectively. As the prognosis of patients with prostate sarcoma who underwent only surgery was poor, they proposed that multimodal therapy should be performed. Of the six patients with stage Ⅲ prostate sarcoma treated with preoperative chemotherapy and/or radiation therapy, four survived and were with disease-free at mean time of 70 months. 5 Agents used for neoadjuvant chemotherapy included combination of gemcitabine and docetaxel; doxorubicin and ifosfamide; or cyclophosphamide, vincristine, and doxorubicin. 6 Recently, Ball et al. 7 reported that preoperative chemoradiation therapy for eight patients (three with LMSOP) with stage Ⅲ, high-grade prostate sarcoma improved OS. Neoadjuvant radiotherapy was administered at 45-50.4 Gy. The MAI (mesna, doxorubicin, and ifosfamide) was administered as concurrent chemotherapy. The median OS was 67.8 months, and the survival rate at 1,3,5 years were 100%, 55.6%, and 55.6%, respectively. All three LMSOP patients were survived.
Ogura et al. 8 reported that perioperative chemotherapy with a modified MAID regimen resulted in a favorable outcome for patients with high-grade non-small round cell soft sarcomas. Among the 26 patients evaluated, 8 achieved a partial response, 15 had stable disease, and 3 patients showed disease progression. The 5-year OS and disease-free survival rates were 86% and 77%, respectively. Grade 3/4 hematopoietic toxicity, especially neutropenia (95%) was frequently observed, but no other serious adverse events were noted. Therefore, we concluded that the MAID regimen is one of the most appropriate neoadjuvant chemotherapy for patients with LMSOP.

Conclusion
A multimodal approach, including systemic chemotherapy and radical surgery, should be considered to achieve a longterm survival of patients with localized prostate leiomyosarcoma.