Post Radiotherapy Leiomyosarcoma of the Prostate: Can Radiation Therapy Induce a Secondary Cancer? A Case Report

Sharon Yee¹, Michael J. Goldfischer², Richard J. Rosenbluth³, Donald A. McCain⁴, Imani Jackson⁵, Ihor S. Sawczuk⁶

¹University of Medicine and Dentistry New Jersey Medical School
²Department of Pathology, Hackensack University Medical Center
³ John Theurer Cancer Center at Hackensack University Medical Center
⁴John Theurer Cancer Center at Hackensack University Medical Center
⁵Division of Urology, University of Medicine and Dentistry New Jersey Medical School
⁶Department of Urology, Hackensack University Medical Center
  Correspondence should be addressed to Sharon Yee, yeesh@umdnj.edu 

Introduction:

Sarcoma of the prostate is a rare neoplasm, accounting for less than 0.1% of prostate malignancies with only a few cases reported to date. As a whole, sarcomas account for 1% of all malignant tumors and less than 5% of them arise from the genitourinary system [1]. The two most common subtypes are leiomyosarcoma and rhabdomyosarcoma, the former being most common in adults while the latter more commonly seen in the pediatric population [2].   Leiomyosarcoma accounts for 38 to 52% of primary prostatic sarcomas and the etiology remains yet to be discovered [3].  The prognosis for this cancer is poor and the average survival is variable with a median survival of 17 to 24 months [4,5].  We present a case report on a patient diagnosed with prostate sarcoma following initial diagnosis and treatment for adenocarcinoma of the prostate. 

Case Report:

A 75 year old male with a history of diabetes, hypertension, hyperlipidemia, coronary artery disease, and a history of radiation failed prostate adenocarcinoma presented with hematuria and was found to have a mass on digital rectal exam.  Patient was diagnosed with prostate adenocarcinoma 8 years prior, which was staged at T2b.  There was no family history of any genitourinary cancer, and patient was an exsmoker and denied alcohol abuse.  At the time of initial diagnosis, patient was treated with external beam radiation therapy and brachytherapy that consisted of palladium seed implantation.  Both treatments locally failed with an increasing PSA and four years later, the patient underwent cryosurgical ablation without complications. Immediately prior to cryoablation, all 12 prostate biopsies showed poorly differentiated adenocarcinoma with a Gleason score of 4+5=9.  It was clinically staged as T2b, and body bone scan and CAT scan of abdomen and pelvis was negative for metastases.  Digital rectal exam prior to cryoabation revealed a small irregular prostate with mild induration over both lobes.  PSA at that time was 11.4 with a prostate volume of 26 cc.  Right after cryoablation, PSA decreased to 0.2. 

However, the PSA slowly trended upward to 1.5 one year later and then two years after cryoablation to 2.7 with a questionable induration at the prostatic base on DRE.  CAT scan confirmed a 2.3 cm mass along the anterior surface of the rectum just posterior to the seminal vesicles.  At this time hormonal therapy was initiated due to high likelihood of recurrence of disease.  Hormone therapy consisted of Leuprolide Depot 30mg every 4 months and Bicalutamide 50mg, which successfully controlled the disease with a PSA decline back down to 0.1 after 8 months or two doses of Lupron treatments.  DRE at that time was negative with a flat benign feeling prostate.  Patient’s PSA continued to hold steady at 0.1 on hormone therapy, but two years after starting hormone therapy, patient complained of gross hematuria with frequency.  On DRE, prostate was indurated and slightly enlarged at 30 grams, and PSA was 0.1.  A hematuria work up was completed.  Cystoscopy revealed a large median lobe that was partially necrotic and oozing blood.   CT urogram revealed a marked increase in size of the pelvic neoplasm with direct invasion of the rectum measuring 8.3 x 5cm.  There was no pelvic sidewall or retroperitoneal lymphadenopathy.  Prostate biopsies revealed infiltrative, interlacing fascicles of spindle cells with eosinophilic cytoplasm characterized by high cellularity, marked nuclear atypia and numerous atypical mitosis, which was strongly suggestive of prostate sarcoma.  Immunostaining of the biopsies were negative for PAS, PCA3, CK A1/A3, CK903, PSA and hormone receptor ER/PR ruling out any residual epithelial prostate adenocarcinoma.  Immunostains for leiomyosarcoma were positive.  Desmin and Smooth Muscle Actin was weakly positive, Vimentin was strongly positive.  Thus, confirming a diagnosis of prostate leiomyosarcoma.

The patient underwent a radical cystoprostatectomy, bilateral pelvic lymph node dissection, resection of left sigmoid and rectum, ileal conduit urinary diversion, and colostomy uneventfully.  Pathology revealed a high grade leiomyosarcoma of the prostate.  The tumor completely replaced the prostate and extended into the periprostatic adipose tissue and bladder wall.  Perineural invasion was present without angiolymphatic invasion.  The tumor extended posteriorly into the deep pelvic tissue including through the full thickness of the rectum.  Tumor was present at the posterior margin of the prostate, and subsequent rectal deep margin.  However, additional deep margin was taken separately, which was free at the designated ink margins.  The prostatic apex was also positive, and no additional tissue was submitted.  The resected rectum specimen showed diffuse infiltration by high grade leiomyosarcoma with tumor infiltration throughout the full thickness of the bowel wall and presence of ulcerations through the free mucosal surface (figure 1).  The sigmoid colon and pelvic lymph nodes were negative for tumor.  A panel of immunohistochemical stains performed supported the diagnosis of a malignant smooth muscle neoplasm based on the positive staining for smooth muscle actin and desmin (figure 2).  The other malignant entities in the differential including other mesenchymal neoplasms and a sarcamatoid carcinoma were ruled out with negative staining for myogenin, S100, CD34, HMW cytokeratin, and pancytokeratin.

Post-operatively, the patient was followed by an oncologist.  The oncologist’s treatment plan included observation through CAT scans every 3 months.   Three months after the surgery, a CT of the abdomen, chest, and pelvis with contrast showed a new 3 mm nodule in the right middle lobe, representing metastasis.  In addition, there was soft tissue in the region adjacent to the prostate bed and rectal stump which was suspicious for tumor recurrence.  Soon after patient developed an infection, so chemotherapy was started after infection resolved which consisted of a dose of Doxil every two weeks, in which dosage was adjusted according to weight and height.  Radiation therapy was not a treatment option since sarcomas do not respond to radiation.  A CT with contrast several months later showed increased findings.  The soft tissue located near the prostate bed had a marked increase in size with the mass invading into the perineum and abdominal wall that led to a cutaneous fistula.  There were also numerous new pulmonary metastases identified in the lung bases.  Patient also had a urinary tract infection in addition to an infection in the fistula and was hospitalized.  Doxil was discontinued until infection resolves and fistula heals.  As of current date, the patient is being withheld from chemotherapy while awaiting fistula to resolve.  Patient is alive, and it has been at least 17 months since complaint of gross hematuria, and the overall prognosis for the patient is poor.

Discussion:

Leiomyosarcoma of the prostate is a rare prostate malignancy with a poor prognosis secondary to aggressiveness of tumor growth, lack of early symptoms and late presentation.  However, the survival rate is variable and can range from 0 to 60% and survival length ranges from months to years.  It is reported that 50-75% of patients die of prostatic leiomyosarcoma after 2 to 5 years [6].  Recommended treatment for prostate leiomyosarcoma is surgery involving a cystoprostatectomy followed by chemotherapy or radiotherapy [2].   Surgery may serve as symptomatic relief and as a palliative option for patients as opposed to a cure, since local recurrence and metastasis is common.  There is no optimal form of therapy, but Mansouri et al states that radical surgery with complete resection offers a chance for prolonged survival when the tumor has low mitotic activity [7].   Additionally, Dotan et al.’s study demonstrates that complete surgical resection can lead to decreased local recurrence and decrease metastasis, which prolonged survival [8].   Unfortunately, as mentioned above, prostate leiomyosarcoma is often caught late in the disease process, so tumor size at time of surgical resection is commonly extensive as in our patient’s case.  Thus, it is believed that variables that may affect disease survival are tumor margins, size, grade, histology, and complete tumor resection.  However, further research is needed because there is contradicting evidence in the literature.  Sexton et al reported no association between negative surgical margins, tumor size and staging with survival [9,10].  

In respects to adjuvant therapy, Sexton et al and Janet et al studies have shown that there may be a survival advantage for combined multimodality approach versus surgery by itself, and thus recommends optimizing multimodality treatment strategies to improve prognosis [4,10].   Nonetheless, studies have shown that rare prostatic carcinomas that develop after radiation therapy are usually aggressive tumors that present with secondary deposits, in which the outcome is generally poor regardless of treatment.  Additionally, since sarcomas have a high recurrence rate, it is recommended for patients to be followed closely with chest, abdominal, and pelvic imaging.  Primary sites of metastases in order of frequency are lung, bone, lymph nodes, and brain [11].

There is no definite known etiology for the development of prostate leiomysarcoma, and there has been an ongoing debate on whether radiation therapy to the prostate can induce a secondary cancer.  In the presented case report, leiomyosarcoma of the prostate was discovered 8 years after treatment for prostate adenocarcinoma that consisted of a failed brachytherapy and failed external beam therapy, and eventually cryoablation.  It is interesting to note that the patient presented in our case report is not the only one to have developed a leiomyosarcoma of the prostate after various radiation therapies to the prostate.  In fact, a handful of cases in the literature were found associating adenocarcinoma and leiomyosarcoma of the prostate.  A study completed by Moreira et al. suggests a causal effect of leiomyosarcoma of the prostate following brachytherapy to the prostate.  The study discussed complications after brachytherapy, in which three patients developed cancer of the prostate status post brachytherapy.  One developed recurrence of the adenocarcinoma, and two others developed secondary cancers.  They were a neuroendocrine tumor of the rectum and leiomyosarcoma of the prostate [12].  In addition, McKenzie et al. reported three cases of postirradiation sarcoma that arose in the pelvis 8, 15, and 16 years later after external beam therapy to treat localized adenocarcinoma of the prostate [13].  Prevost et al. reported one case of postirradiation sarcoma that developed in the right inguinal region 8 years after external beam therapy for localized prostate adenocarcinoma [5].  Mazzucchelli and colleagues’ study on histological variants of prostatic carcinoma reported that half the cases of sarcomatous component (SC) carcinosarcoma of the prostate had developed after hormonal or radiation therapy for an initial diagnosis of acinar adenocarcinoma.  However, SC status post radiation therapy is not necessarily the only cause, since SC’s can develop de novo [11].  

In terms of leiomyosarcomas developing in other regions of the body after local radiation, Grabowska et al. reviewed 11 cases of leiomyosarcomas of the head and neck developing post-irradiation to those areas [14].   In addition, Olcina et al. describes the development of radiation-induced sarcoma post-mastectomy treatment.  The article reports that the frequency of newly diagnosed sarcomas is rising in relation with increasing survival of breast cancer patients treated with adjuvant radiation therapy [15].

Thus, further studies need to be completed to assess whether there is a link between radiation therapy to the prostate and the development of leiomyosarcoma of the prostate.  If such an association exists, it may be beneficial to closely monitor radiation treated  prostate cancer patients, who may appear to be locally controlled and consider early re-biopsy.  Studies have shown that a PSA level proves to be a poor marker of screening for prostate leiomyosarcoma, just as in the patient discussed in this article, who had a PSA of 0.1 on diagnosis of leiomyosarcoma.  Therefore, initial suspicion for prostate leiomyosarcoma should be based on symptoms such as hematuria, pelvic and back pain and mass on digital rectal exam.  However, the rarity of the cancer and the little evidence in literature would argue against any type of necessary screening.  Nonetheless, leiomyosarcoma of the prostate is an aggressive tumor, and the best treatment outcomes lay in early detection.

References:

1. Vandoros GP, Manolidis T, Karamouzis MV, Gkermpesi M, et al.  Leiomyosarcoma of the Prostate: Case Report and Review of 54 Previously Published Cases.  Sarcoma.  2008;2008:458079.Epub 2008 Nov 18.
2. Agarwal NK, Dorairajan LN, Kumar S, Murthy C, Krishnan R.  Primary prostatic leiomyosarcoma in an adult.  Indian J Urol. 2006 Mar;22(1):66-7.
3. Mondani N, Palli D, Saieva C, et al.  Clinical characteristics and overall survival in genitourinary sarcomas treated with curative intent: a multicenter study.  Eur Urol. 2005;47(4):468-473.
4. Janet NL, May AW, Akins RS.  Sarcoma of the prosate: a single institutional review.  Am J Clin Oncol. 2009 Feb;32(1):27-9.
5. Prevost JB, Bossi A, Sciot R, Debiec-Rychter M.  Post-irradiation sarcoma after external beam radiation therapy for localized adenocarcinoma of the prostate.  Tumori. 2004 Nov-Dec;90(6):618-21.
6. Miedler JD, MacLennan GT.  Leiomyosarcoma of the prostate.  J Urol. 2007 Aug;178(2):668.
7. Mansouri H, Kanouni L, Kebdani T, Hassouni K, Sifat H, El Gueddari B.  Primary prostatic leiomyosarcoma.  J Urol. 2001 May;165(5):1676.
8. Dotan ZA, Tal R, Golijanin D, Snyder ME, Antonescu C, Brennan MF, Russo P.  Adult genitourinary sarcoma: the 25-year memorial sloan-kettering experience.  J Urol. 2006 Nov;176(5):2033-39.
9. Cheville JC, Dundore PA, Nascimento AG, Meneses M, Kleer E, Farrow GM, Bostwick DG.  Leiomyosarcoma of the prostate report of 23 cases.  Cancer. 1995 Oct 15;76(8):1422-7.
10. Sexton WJ, Lance RE, Reyes AO, et al.  Adult prostate sarcoma: the MD Anderson Cancer Center experience.  J Urol. 2001;166:521-525.
11. Mazzucchelli R, Lopez-Beltran A, Cheng L, Scarpelli M, Kirkali Z, Montironi R.  Rare and unusual histological variants of prostatic carcinoma: clinical significance.  BJU Int. 2008 Nov;102(10):1369-74. Epub 2008 Sep 12.
12. Moreira SG Jr, Seigne JD, Ordorica RC, Marcet J, Pow-Sang JM, Lockhart JL.  Devastating complications after brachytherapy in the treatment of prostate adenocarcinoma.  BJU Int. Jan 2004;93(1):31-5.
13. McKenzie M, MacLennan I, Kostashuk E, Bainbridge T.  Postirradiation sarcoma after external beam radiation therapy for localized adenocarcinoma of the prostate: report of three cases.  Urology. 1999 Jun;53(6):1228.
14. Grabowska SZ, ZimnochL, Hubert E, Duraj E, Wincewicz-Pietrzykowska A.  Radiation induced leiomyosarcoma. Review of literature and case report.  Otolaryngol Pol. 2007;61(5):744-9.
15. Olcina M, Merck B, Giménez-Climent MJ, et al. Vázquez-Albadalejo C.  Radiation-induced leiomyosarcoma after breast cancer treatment and TRAM flap reconstruction.  Sarcoma. 2008;456950.