- Email: [email protected]
Metastatic Primitive Neuroectodermal Tumor of the Prostate: A Case Report and Review of the Literature
Case Report
Metastatic Primitive Neuroectodermal Tumor of the Prostate: A Case Report and Review of the Literature Ali Kord Valeshabad,1,2 Paul Choi,1 Nour Dababo,1 Ejaz Shamim,1 Alaa Alsadi,3 Karen L. Xie1 Clinical Practice Points Peripheral primitive neuroectodermal tumor (PNET) is
Review of the previously reported cases revealed a
a rare malignant neural crest tumor that is now included in the Ewing family of tumors. PNET is specifically thought to be related to Ewing sarcoma, sharing overlapping cytogenetic features and translocation. Although Ewing sarcoma often occurs in the soft tissue and bones of children, very rare cases of PNET in the bladder, prostate, kidney, and adrenal gland have been reported. A 38-year-old male presented with a lower abdominal pain and hematuria for 2 months. Computed tomography and magnetic resonance imaging showed a large pelvic mass, suspicious of malignancy with evidence of local invasion and distant metastasis. Biopsy confirmed PNET of the prostate, and the patient underwent chemotherapy and surgical resection with a survival of 14 months.
young age at presentation with a mean SD of 28.3 8.0 years (N ¼ 10; range, 20-49 years). Forty percent of the patients presented with metastatic disease, with the lung being the most common site for the metastasis. Ninety percent of patients received chemotherapy, whereas 3 out of 8 patients received radiotherapy, and 50% (4 of 8 patients) underwent surgery. The survival was 10.4 8.6 years (N ¼ 5; range, 2-24 months; median, 10 months). PNET of the prostate involves young male adults, may present as metastatic disease, and has poor outcomes, with a median survival of less than 1 year despite multimodal treatment strategy of the combination of chemotherapy, radiotherapy, and surgical resection.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Ewing family of tumors, Ewing sarcoma, Malignant neural crest tumor, Magnetic resonance imaging, Staging
Introduction Peripheral primitive neuroectodermal tumor (PNET) is a rare malignant neural crest tumor that is now included in the Ewing family of tumors. PNET is specifically thought to be related to Ewing sarcoma (ES) as they have been found to share overlapping cytogenetic features and translocation of t(11;22)(q24;q12).1 P.C. and N.D. contributed equally to this article.
Although ES often occurs in the soft tissue and bones of children, very rare cases of PNET in the bladder, prostate, kidney, and adrenal gland have been reported.2-5 To our knowledge, there have been 10 reported cases of PNET of the prostate.4,6-14 Patients with PNET of the prostate typically undergo a combination of chemotherapy, radiotherapy, and surgery but often suffer poor outcomes. In this study, we present an extremely rare case of metastatic PNET of the prostate with a brief review of the current literature.
1
Department of Radiology Division of Interventional Radiology 3 Department of Pathology, University of Illinois at Chicago, Chicago, IL 2
Submitted: Oct 20, 2017; Accepted: Oct 30, 2017 Address for correspondence: Karen L. Xie, DO, Department of Radiology, University of Illinois at Chicago, 1740 W Taylor St, Chicago, IL 60612 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2017.10.023
Case Report A 38-year-old male with no previous history of malignancy presented to the urology clinic at the University of Illinois at Chicago with complaint of lower abdominal pain, constipation, pain with defecation, and hematuria for about 2 months. There was no reported weight loss. Physical examination revealed a soft,
Clinical Genitourinary Cancer Month 2017
-1
PNET of the Prostate Figure 1 Coronal Computed Tomography (CT) of the Abdomen and Pelvis With Contrast at Presentation (A) Demonstrates a Heterogeneous Mass Within the Pelvis Abutting the Urinary Bladder With Bilateral Mild to Moderate Hydronephrosis. Bilateral Ureteral Stents Are Partially Visualized. Coronal Contrast-enhanced CT of the Chest, Abdomen, and Pelvis (B) Demonstrates Multiple Metastases (White Arrows) Within the Lungs, Liver, and Peritoneum. Post-chemotherapy CT Imaging Shows Favorable Response to the Treatment With Improvement of the Pulmonary (Partially Shown), Hepatic and Peritoneal Metastases
2
-
nondistended abdomen and no inguinal lymphadenopathy. Digital rectal examination revealed a firm mass fixed anteriorly with distal extension to the superior portion of the ano-rectal ring. Biochemical investigations demonstrated slight elevation of the transaminases and white blood cell counts. A computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast revealed a heterogeneous mass measuring 11.1 11.3 14.4 cm arising from the prostate and abutting the bladder. Nodular implants suspicious for metastases were noted on the omentum, peritoneum, and bladder (Figure 1). Magnetic resonance imaging (MRI) of the pelvis confirmed a lobulated mass replacing the prostate and seminal vesicles, occupying a large portion of the pelvis. The mass appeared hypointense on T1-weighted images and heterogeneously isointense to hyperintense on T2-weighted images. Tumor invasion was noted on the posterior bladder wall and right wall of the rectosigmoid colon (Figure 2). A transrectal biopsy of the mass was performed. Microscopic examination revealed a poorly differentiated neoplasm demonstrating focal neuro-ectodermal morphology (Homer Wright rosettes) as well as focal membranous staining for CD99 by immunohistochemical studies (Figure 3). Molecular pathology analysis revealed an EWSR1/FLI1 fusion transcript confirming a final diagnosis of PNET. The patient was scheduled for resection of the prostatic mass. However, a colonic perforation occurred while the patient was awaiting the procedure, necessitating a bowel resection with colostomy. The patient subsequently presented to the emergency room with worsening pain, and an abdominal CT and chest radiograph revealed a rapidly growing pelvic tumor with metastases to the
Clinical Genitourinary Cancer Month 2017
liver and lung. Bilateral hydronephrosis was also noted secondary to mass effect causing ureteral obstruction, requiring bilateral nephrostomy. The medical team arrived at a multidisciplinary decision to initiate chemotherapy prior to surgery. Pelvic exenteration was performed after several rounds of chemotherapy with cyclophosphamide, doxorubicin, and vincristine, which was complicated by fever, neutropenia, and recurrent urinary tract infection. Pathology studies of the surgical specimens demonstrated extraprostatic tumor extension to the muscular layer of the bladder, with negative tumor involvement in the peritoneum, small bowel, colon, and ureters. An aggressive treatment approach was adopted, stem cell harvest was performed, and chemotherapy was reinitiated prior to planned radiotherapy. However, after 6 rounds of chemotherapy, the patient subsequently developed sepsis and ultimately expired after hemodynamic deterioration.
Previous Cases of PNET of the Prostate Table 1 summarizes the demographics and clinical data of previously reported cases of PNET of the prostate. The mean standard deviation (SD) age of the reported cases was 28.3 8.0 years (N ¼ 10; range, 20-49 years). Forty percent of the patients presented with imaging evidences of metastatic disease, with lung being the most common site for the metastasis. The pathologic evaluation was available in 6 cases and demonstrated stage T2b in all cases, defined as having a tumor > 5 cm in largest dimension in the deep tissue. Four of the 10 cases demonstrated findings suspicious for metastases. The pathologic staging in the other 4 cases could not be determined from the reports alone.
Ali Kord Valeshabad et al Figure 2 Axial T1 (A) and T2 (B) Weighted Magnetic Resonance Imaging (MRI) Images of the Pelvis Show a Large Mass Within the Pelvis that is Hypointense on T1-weighted Images and Heterogeneously Isointense to Hyperintense on T2-weighted Images. Postcontrast Axial (C) and Coronal (D) T1-Weighted Images With Fat Saturation Demonstrate a Heterogeneously Enhancing Mass With Local Invasion to the Posterior Urinary Bladder Wall (White Arrow, C) and Right Wall of the Rectosigmoid Colon (White Arrow Head, D)
Nine of the 10 cases utilized neoadjuvant or adjuvant chemotherapy (1 of the reports did not detail their treatment). Four of 8 patients underwent surgical treatment with radical prostatectomy, and 3 of them underwent radiation therapy. Chemotherapy medications in previous studies included a combination of ifosfamide, etoposide, vincristine, adriamycin, doxorubicin, actinomycin, docetaxel, gemcitabine, and cyclophosphamide. The mean survival time was 10.4 8.6 months (N ¼ 5; range, 2-24 months; median, 10 months). The longest reported survival was 24 months in a patient with an initial imaging stage of T2b NX M0, in which positron emission tomography scan demonstrated no distant metastases. The patient received vincristine, adriamycin, cylcophosphamide, ifosfamide, and etoposide with radiation therapy.
Discussion Demographics and Presentation PNET of the prostate is an extremely rare malignancy, and is one of the most aggressive tumors with a very poor prognosis.14 Based on the previously reported cases, this malignancy involves young males from 20 to 50 years old. Patients with PNET of the prostate may present with pelvic pain, dysuria, hematuria, urinary retention,
difficulty defecating, anal distention, anal pain, and hematochezia.12,14 Our literature review showed that about 40% of the patients with PNET of the prostate present with distant metastases. The lung is the most common site of distant metastasis, and all patients with metastatic cancer had at least pulmonary metastasis at presentation. The patient in our study presented with lower abdominal pain, constipation, pain with defecation, and hematuria and had more advanced disease at presentation, with metastases to the lung, liver, bone, and peritoneum in addition to local invasion of the bladder and colon.
Imaging Findings CT and MRI play the main role in diagnosis, assessment of the local invasion and distant metastasis, pretreatment staging, and posttreatment follow-up. Among the previously reported 10 cases, the presenting tumors have been described as a multilobulated mass, a heterogeneously enhancing mass, and a mass that replaced the prostate gland in CT and MRI,4,6-14 similar to our patient. On MRI, as was seen in our study, the lesion is usually hypointense on T1-weighted images, heterogeneously isointense to hyperintense on T2-weighted images, and demonstrates heterogeneous enhancement
Clinical Genitourinary Cancer Month 2017
-3
PNET of the Prostate Figure 3 Low Power View of the Tumor (A). Note the Extension to the Extraprostatic Adipose Tissue (Right and Upper) as Well as the Muscular Layer of the Bladder (Area in Red Dotted Line). 253 Magnification. Hematoxylin and Eosin Stain. Higher Power View (B) Shows Uniform Small Round Blue Cells With Scant Cytoplasm, Indistinct Cytoplasmic Boarders, and Nuclei Containing Fine Chromatin. Some Degree of Neuroectodermal Differentiation (Ill-defined Groups of Cells Oriented Toward a Central Space) is Present. 2003 Magnification. Hematoxylin and Eosin Stain. Tumor Cells are Positive for CD99 Antibodies in a Membranous Fashion (C). 4003 Magnification. CD99 Immunostain
on post-contrast imaging.4,7,13,14 MRI is more sensitive to evaluate local invasion of the tumor. In our case, there was local invasion to the posterior bladder base, and anterior wall of the rectosigmoid colon demonstrated on MRI. In 5 reported cases,4,8-10,14 there was displacement or involvement of the bladder wall on imaging, 4 of which revealed metastases to distant sites. Four cases had involvement or close association of tumor with seminal vesicles4,7,9,14; only 1 of them demonstrated distant metastases.14 In addition, there was 1 study that demonstrated tumor involvement of the left ureter and bladder wall with bilateral hydroureteronephrosis that showed no evidence of metastases.9 CT imaging is more useful to assess distant metastasis. In patients with PNET of the prostate, distant
metastases to the lung, bone, and intracranial meninges have been reported.8,10,12,14 The patient in our study had more extensive metastases to the omentum, peritoneum, liver, and lungs and local invasion to the rectosigmoid colon and bladder.
Pathologic Findings According to the College of American Pathologists, ES/PNET tumors are positive for CD99/MIC-2 in almost all cases, and approximately 90% to 95% of ES/PNET are positive for the EWS-FLI1 fusion gene. The presence of the t(11;22) (EWS-FLI1) and t(21;22) (EWS-ERG) are strongly correlated with ES/PNET, but are not required to make the diagnosis.15 In all previous
Table 1 Demographics and Clinical Data of Previously Reported Cases With Primitive Neuroectodermal Tumor of the Prostate
4
-
#
Author
Age, y
Metastases
Chemotherapy
1
Colecchia et al7
31
None
2
Peyromaure et al11
27
None
3 4
Thete et al13 Kumar et al9
26 25
None None
5 6
Funahashi et al8 Mohsin et al10
20 29
Lung Lung
7
Al Haddabi et al6
24
None
8 9
Wu et al14 Shibuya et al12
29 23
10
Liao et al4
49
Lung Bone, lung, meninges None
Ifosfamide, etoposide, vincristine, adriamycin Ifosfamide, etoposide, vincristine, doxorubicin N/A Ifosfamide, vincristine, actinomycinD, adriamycin Ifosfamide Vincristine, doxorubicin; docetaxel, gemcitabine; ifosfamide Ifosfamide, doxorubicin, vincristine, etoposide Multi-agent (detail N/A) Ifosfamide
11
Current case
38
Lung, liver, bone, peritoneum
Vincristine, adriamycin, ifosfamide, cyclophosphamide, etoposide Cyclophosphamide, doxorubicin, etoposide
Abbreviations: CT ¼ computed tomography; MRI ¼ magnetic resonance imaging; N/A ¼ Not available.
Clinical Genitourinary Cancer Month 2017
Radiation Surgery
Survival, mos
Stage
Yes
Yes
N/A
Yes
Yes
2
T2b NX MX Pathologic Unknown
N/A N/A
N/A N/A
N/A N/A
NA T2b NX MX CT
No No
Yes No
10 N/A
T2b NX M1 MRI NA/Unknown
No
No
N/A
T2b NX MX MRI
No No
Yes No
12 4
T2b NX M1 MRI NA/Unknown
Yes
No
24
T2b NX MX CT
No
Yes
14
T2b NX M1 CT
Ali Kord Valeshabad et al 10 cases with PNET of the prostate, round small cells that stained positively for CD99 (MIC-2) were confirmed on histology and immunohistochemistry studies, although there was variable demonstration of Homer-Wright Rosette structure, neuron-specific enolase, vimentin, synaptophysin, and cytokeratin across all studies. Five studies performed molecular studies (either fluorescent in situ hybridization or real-time polymerase chain reaction) searching for the ES/PNET translocation.6-8,11,12 Four of 5 of these reports demonstrated the ES/PNET translocation.6-8,11 Our case was similar to these studies in that there was translocation t(11;22)(q24;q12), small cells that stained positively for CD99, and presence of Homer-Wright Rosettes. However, immunohistochemistry did not demonstrate staining for synaptophysin, neuron-specific enolase, and vimentin. The histologic findings, immunohistochemistry, and molecular real-time polymerase chain reaction studies together confirm PNET disease belonging to the Ewing family of tumors.
Staging Currently, the staging of PNET/ES is based on TNM staging systems for primary tumors of both bone and soft tissue available from the American Joint Committee on Cancer/Union for International Cancer Control, but no widely accepted system exists specifically for the Ewing family of tumors (EFT). However, the American Joint Committee on Cancer/Union for International Cancer Control and the College of American Pathologists currently use the TNM staging system for soft tissue sarcomas for extraosseous ES.15 Based on our review, all 6 cases with known pathologic results demonstrated stage T2b of PNET of the prostate, defined as having a tumor > 5 cm in the largest dimension in the deep tissue. Four of the 10 cases demonstrated findings suspicious for metastases. The pathologic staging in the other 4 cases could not be determined from the reports alone.
Treatment and Outcome Treatment for EFTs involves a combination of systemic chemotherapy, radiation therapy, and surgical resection. A multimodal treatment strategy was used in all previous 10 cases of PNET of the prostate. Nine of the 10 cases utilized neoadjuvant or adjuvant chemotherapy (one of the reports did not detail their treatment).4,6-12,14 Four of 8 patients underwent surgical treatment with radical prostatectomy,7,8,11,14 and 3 of them underwent radiation therapy.4,7,11 Chemotherapy medications in previous studies included a combination of ifosfamide, etoposide, vincristine, adriamycin, doxorubicin, actinomycin, docetaxel, gemcitabine, and cyclophosphamide. The longest reported survival was 24 months after initial diagnosis by Liao et al.4 The patient in that study had imaging stage of T2b NX M0, the positron emission tomography scan demonstrated no distant metastases, and the patient received vincristine, adriamycin, cylcophosphamide, ifosfamide, and etoposide with radiation therapy. The patient in our study presented with late-stage metastatic disease and underwent chemotherapy with
cyclophosphamide, doxorubicin, and etoposide. The chemotherapy was effective, resulting in almost complete resolution of the lung metastases, and marked improvement in hepatic and bone metastases. The pelvic tumor was found to be smaller in size. After 6 rounds of chemotherapy, our patient underwent surgical pelvic exenteration, but subsequently developed sepsis and ultimately expired after hemodynamic deterioration. There is no established chemotherapeutic regimen for EFTs, particularly PNET of the prostate, and a specific regimen that may influence response to treatment remains to be investigated.
Conclusion In summary, an extremely rare case of metastatic PNET of the prostate is described in this case report. PNET of the prostate involves young male adults, may present as metastatic disease, and has poor outcomes with a survival of less than 1 year despite multimodal treatment strategy with the combination of chemotherapy, radiotherapy, and surgical resection.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Jpn J Clin Oncol 2007; 37:79-89. 2. Dutta D, Shivaprasad KS, Das RN, Ghosh S, Chowdhury S. Primitive neuroectodermal tumor of adrenal: clinical presentation and outcomes. J Cancer Res Ther 2013; 9:709-11. 3. Lam CJ, Shayegan B. Complete resection of a primitive neuroectodermal tumour arising in the bladder of a 31-year-old female after neoadjuvant chemotherapy. Can Urol Assoc J 2016; 10:E264-7. 4. Liao C, Wu X, Wang X, Li H. Primitive neuroectodermal tumor of the prostate: case report from China. J Cancer Res Ther 2015; 11:668. 5. Parakh R, Parakh S, Tretiakova M. Primitive neuroectodermal tumor and Wegener’s granulomatosis of the kidney: a curious combination of two rare entities. Case Rep Urol 2017; 2017:1750694. 6. Al Haddabi I, Al Bahri M, Burney I. Cytokeratin-positive primitive neuroectodermal tumor of the prostate: case report and review of literature. Indian J Pathol Microbiol 2012; 55:569-71. 7. Colecchia M, Dagrada G, Poliani PL, Messina A, Pilotti S. Primary primitive peripheral neuroectodermal tumor of the prostate. Immunophenotypic and molecular study of a case. Arch Pathol Lab Med 2003; 127:e190-3. 8. Funahashi Y, Yoshino Y, Hattori R. Ewing’s sarcoma/primitive neuroectodermal tumor of the prostate. Int J Urol 2009; 16:769. 9. Kumar V, Khurana N, Rathi AK, et al. Primitive neuroectodermal tumor of prostate. Indian J Pathol Microbiol 2008; 51:386-8. 10. Mohsin R, Hashmi A, Mubarak M, et al. Primitive neuroectodermal tumor/Ewing’s sarcoma in adult uro-oncology: A case series from a developing country. Urol Ann 2011; 3:103-7. 11. Peyromaure M, Vieillefond A, Boucher E, et al. Primitive neuroectodermal tumor of the prostate. J Urol 2003; 170:182-3. 12. Shibuya T, Mori K, Sumino Y, Sato F, Mimata H. Rapidly progressive primitive neuroectodermal tumor of the prostate: a case report and review of the literature. Oncol Lett 2015; 9:634-6. 13. Thete N, Rastogi D, Arya S, et al. Primitive neuroectodermal tumour of the prostate gland: ultrasound and MRI findings. Br J Radiol 2007; 80:e180-3. 14. Wu T, Jin T, Luo D, Chen L, Li X. Ewing’s sarcoma/primitive neuroectodermal tumour of the prostate: a case report and literature review. Can Urol Assoc J 2013; 7:E458-9. 15. Carpentieri DF, Bowen J, Krausz T, Qualman SJ, Rubin BP, Hill DA. Protocol for the examination of specimens from patients with primitive neuroectodermal tumor (PNET)/Ewing sarcoma (ES) 2012, Available at: http://www.cap.org/Show Property?nodePath¼/UCMCon/Contribution%20Folders/WebContent/pdf/pnet ewing-12protocol.pdf. Accessed: October 16, 2017.
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Metastatic Primitive Neuroectodermal Tumor of the Prostate: A Case Report and Review of the Literature Ali Kord Valeshabad,1,2 Paul Choi,1 Nour Dababo,1 Ejaz Shamim,1 Alaa Alsadi,3 Karen L. Xie1 Clinical Practice Points Peripheral primitive neuroectodermal tumor (PNET) is
Review of the previously reported cases revealed a
a rare malignant neural crest tumor that is now included in the Ewing family of tumors. PNET is specifically thought to be related to Ewing sarcoma, sharing overlapping cytogenetic features and translocation. Although Ewing sarcoma often occurs in the soft tissue and bones of children, very rare cases of PNET in the bladder, prostate, kidney, and adrenal gland have been reported. A 38-year-old male presented with a lower abdominal pain and hematuria for 2 months. Computed tomography and magnetic resonance imaging showed a large pelvic mass, suspicious of malignancy with evidence of local invasion and distant metastasis. Biopsy confirmed PNET of the prostate, and the patient underwent chemotherapy and surgical resection with a survival of 14 months.
young age at presentation with a mean SD of 28.3 8.0 years (N ¼ 10; range, 20-49 years). Forty percent of the patients presented with metastatic disease, with the lung being the most common site for the metastasis. Ninety percent of patients received chemotherapy, whereas 3 out of 8 patients received radiotherapy, and 50% (4 of 8 patients) underwent surgery. The survival was 10.4 8.6 years (N ¼ 5; range, 2-24 months; median, 10 months). PNET of the prostate involves young male adults, may present as metastatic disease, and has poor outcomes, with a median survival of less than 1 year despite multimodal treatment strategy of the combination of chemotherapy, radiotherapy, and surgical resection.
Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Ewing family of tumors, Ewing sarcoma, Malignant neural crest tumor, Magnetic resonance imaging, Staging
Introduction Peripheral primitive neuroectodermal tumor (PNET) is a rare malignant neural crest tumor that is now included in the Ewing family of tumors. PNET is specifically thought to be related to Ewing sarcoma (ES) as they have been found to share overlapping cytogenetic features and translocation of t(11;22)(q24;q12).1 P.C. and N.D. contributed equally to this article.
Although ES often occurs in the soft tissue and bones of children, very rare cases of PNET in the bladder, prostate, kidney, and adrenal gland have been reported.2-5 To our knowledge, there have been 10 reported cases of PNET of the prostate.4,6-14 Patients with PNET of the prostate typically undergo a combination of chemotherapy, radiotherapy, and surgery but often suffer poor outcomes. In this study, we present an extremely rare case of metastatic PNET of the prostate with a brief review of the current literature.
1
Department of Radiology Division of Interventional Radiology 3 Department of Pathology, University of Illinois at Chicago, Chicago, IL 2
Submitted: Oct 20, 2017; Accepted: Oct 30, 2017 Address for correspondence: Karen L. Xie, DO, Department of Radiology, University of Illinois at Chicago, 1740 W Taylor St, Chicago, IL 60612 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clgc.2017.10.023
Case Report A 38-year-old male with no previous history of malignancy presented to the urology clinic at the University of Illinois at Chicago with complaint of lower abdominal pain, constipation, pain with defecation, and hematuria for about 2 months. There was no reported weight loss. Physical examination revealed a soft,
Clinical Genitourinary Cancer Month 2017
-1
PNET of the Prostate Figure 1 Coronal Computed Tomography (CT) of the Abdomen and Pelvis With Contrast at Presentation (A) Demonstrates a Heterogeneous Mass Within the Pelvis Abutting the Urinary Bladder With Bilateral Mild to Moderate Hydronephrosis. Bilateral Ureteral Stents Are Partially Visualized. Coronal Contrast-enhanced CT of the Chest, Abdomen, and Pelvis (B) Demonstrates Multiple Metastases (White Arrows) Within the Lungs, Liver, and Peritoneum. Post-chemotherapy CT Imaging Shows Favorable Response to the Treatment With Improvement of the Pulmonary (Partially Shown), Hepatic and Peritoneal Metastases
2
-
nondistended abdomen and no inguinal lymphadenopathy. Digital rectal examination revealed a firm mass fixed anteriorly with distal extension to the superior portion of the ano-rectal ring. Biochemical investigations demonstrated slight elevation of the transaminases and white blood cell counts. A computed tomography (CT) scan of the abdomen and pelvis with intravenous contrast revealed a heterogeneous mass measuring 11.1 11.3 14.4 cm arising from the prostate and abutting the bladder. Nodular implants suspicious for metastases were noted on the omentum, peritoneum, and bladder (Figure 1). Magnetic resonance imaging (MRI) of the pelvis confirmed a lobulated mass replacing the prostate and seminal vesicles, occupying a large portion of the pelvis. The mass appeared hypointense on T1-weighted images and heterogeneously isointense to hyperintense on T2-weighted images. Tumor invasion was noted on the posterior bladder wall and right wall of the rectosigmoid colon (Figure 2). A transrectal biopsy of the mass was performed. Microscopic examination revealed a poorly differentiated neoplasm demonstrating focal neuro-ectodermal morphology (Homer Wright rosettes) as well as focal membranous staining for CD99 by immunohistochemical studies (Figure 3). Molecular pathology analysis revealed an EWSR1/FLI1 fusion transcript confirming a final diagnosis of PNET. The patient was scheduled for resection of the prostatic mass. However, a colonic perforation occurred while the patient was awaiting the procedure, necessitating a bowel resection with colostomy. The patient subsequently presented to the emergency room with worsening pain, and an abdominal CT and chest radiograph revealed a rapidly growing pelvic tumor with metastases to the
Clinical Genitourinary Cancer Month 2017
liver and lung. Bilateral hydronephrosis was also noted secondary to mass effect causing ureteral obstruction, requiring bilateral nephrostomy. The medical team arrived at a multidisciplinary decision to initiate chemotherapy prior to surgery. Pelvic exenteration was performed after several rounds of chemotherapy with cyclophosphamide, doxorubicin, and vincristine, which was complicated by fever, neutropenia, and recurrent urinary tract infection. Pathology studies of the surgical specimens demonstrated extraprostatic tumor extension to the muscular layer of the bladder, with negative tumor involvement in the peritoneum, small bowel, colon, and ureters. An aggressive treatment approach was adopted, stem cell harvest was performed, and chemotherapy was reinitiated prior to planned radiotherapy. However, after 6 rounds of chemotherapy, the patient subsequently developed sepsis and ultimately expired after hemodynamic deterioration.
Previous Cases of PNET of the Prostate Table 1 summarizes the demographics and clinical data of previously reported cases of PNET of the prostate. The mean standard deviation (SD) age of the reported cases was 28.3 8.0 years (N ¼ 10; range, 20-49 years). Forty percent of the patients presented with imaging evidences of metastatic disease, with lung being the most common site for the metastasis. The pathologic evaluation was available in 6 cases and demonstrated stage T2b in all cases, defined as having a tumor > 5 cm in largest dimension in the deep tissue. Four of the 10 cases demonstrated findings suspicious for metastases. The pathologic staging in the other 4 cases could not be determined from the reports alone.
Ali Kord Valeshabad et al Figure 2 Axial T1 (A) and T2 (B) Weighted Magnetic Resonance Imaging (MRI) Images of the Pelvis Show a Large Mass Within the Pelvis that is Hypointense on T1-weighted Images and Heterogeneously Isointense to Hyperintense on T2-weighted Images. Postcontrast Axial (C) and Coronal (D) T1-Weighted Images With Fat Saturation Demonstrate a Heterogeneously Enhancing Mass With Local Invasion to the Posterior Urinary Bladder Wall (White Arrow, C) and Right Wall of the Rectosigmoid Colon (White Arrow Head, D)
Nine of the 10 cases utilized neoadjuvant or adjuvant chemotherapy (1 of the reports did not detail their treatment). Four of 8 patients underwent surgical treatment with radical prostatectomy, and 3 of them underwent radiation therapy. Chemotherapy medications in previous studies included a combination of ifosfamide, etoposide, vincristine, adriamycin, doxorubicin, actinomycin, docetaxel, gemcitabine, and cyclophosphamide. The mean survival time was 10.4 8.6 months (N ¼ 5; range, 2-24 months; median, 10 months). The longest reported survival was 24 months in a patient with an initial imaging stage of T2b NX M0, in which positron emission tomography scan demonstrated no distant metastases. The patient received vincristine, adriamycin, cylcophosphamide, ifosfamide, and etoposide with radiation therapy.
Discussion Demographics and Presentation PNET of the prostate is an extremely rare malignancy, and is one of the most aggressive tumors with a very poor prognosis.14 Based on the previously reported cases, this malignancy involves young males from 20 to 50 years old. Patients with PNET of the prostate may present with pelvic pain, dysuria, hematuria, urinary retention,
difficulty defecating, anal distention, anal pain, and hematochezia.12,14 Our literature review showed that about 40% of the patients with PNET of the prostate present with distant metastases. The lung is the most common site of distant metastasis, and all patients with metastatic cancer had at least pulmonary metastasis at presentation. The patient in our study presented with lower abdominal pain, constipation, pain with defecation, and hematuria and had more advanced disease at presentation, with metastases to the lung, liver, bone, and peritoneum in addition to local invasion of the bladder and colon.
Imaging Findings CT and MRI play the main role in diagnosis, assessment of the local invasion and distant metastasis, pretreatment staging, and posttreatment follow-up. Among the previously reported 10 cases, the presenting tumors have been described as a multilobulated mass, a heterogeneously enhancing mass, and a mass that replaced the prostate gland in CT and MRI,4,6-14 similar to our patient. On MRI, as was seen in our study, the lesion is usually hypointense on T1-weighted images, heterogeneously isointense to hyperintense on T2-weighted images, and demonstrates heterogeneous enhancement
Clinical Genitourinary Cancer Month 2017
-3
PNET of the Prostate Figure 3 Low Power View of the Tumor (A). Note the Extension to the Extraprostatic Adipose Tissue (Right and Upper) as Well as the Muscular Layer of the Bladder (Area in Red Dotted Line). 253 Magnification. Hematoxylin and Eosin Stain. Higher Power View (B) Shows Uniform Small Round Blue Cells With Scant Cytoplasm, Indistinct Cytoplasmic Boarders, and Nuclei Containing Fine Chromatin. Some Degree of Neuroectodermal Differentiation (Ill-defined Groups of Cells Oriented Toward a Central Space) is Present. 2003 Magnification. Hematoxylin and Eosin Stain. Tumor Cells are Positive for CD99 Antibodies in a Membranous Fashion (C). 4003 Magnification. CD99 Immunostain
on post-contrast imaging.4,7,13,14 MRI is more sensitive to evaluate local invasion of the tumor. In our case, there was local invasion to the posterior bladder base, and anterior wall of the rectosigmoid colon demonstrated on MRI. In 5 reported cases,4,8-10,14 there was displacement or involvement of the bladder wall on imaging, 4 of which revealed metastases to distant sites. Four cases had involvement or close association of tumor with seminal vesicles4,7,9,14; only 1 of them demonstrated distant metastases.14 In addition, there was 1 study that demonstrated tumor involvement of the left ureter and bladder wall with bilateral hydroureteronephrosis that showed no evidence of metastases.9 CT imaging is more useful to assess distant metastasis. In patients with PNET of the prostate, distant
metastases to the lung, bone, and intracranial meninges have been reported.8,10,12,14 The patient in our study had more extensive metastases to the omentum, peritoneum, liver, and lungs and local invasion to the rectosigmoid colon and bladder.
Pathologic Findings According to the College of American Pathologists, ES/PNET tumors are positive for CD99/MIC-2 in almost all cases, and approximately 90% to 95% of ES/PNET are positive for the EWS-FLI1 fusion gene. The presence of the t(11;22) (EWS-FLI1) and t(21;22) (EWS-ERG) are strongly correlated with ES/PNET, but are not required to make the diagnosis.15 In all previous
Table 1 Demographics and Clinical Data of Previously Reported Cases With Primitive Neuroectodermal Tumor of the Prostate
4
-
#
Author
Age, y
Metastases
Chemotherapy
1
Colecchia et al7
31
None
2
Peyromaure et al11
27
None
3 4
Thete et al13 Kumar et al9
26 25
None None
5 6
Funahashi et al8 Mohsin et al10
20 29
Lung Lung
7
Al Haddabi et al6
24
None
8 9
Wu et al14 Shibuya et al12
29 23
10
Liao et al4
49
Lung Bone, lung, meninges None
Ifosfamide, etoposide, vincristine, adriamycin Ifosfamide, etoposide, vincristine, doxorubicin N/A Ifosfamide, vincristine, actinomycinD, adriamycin Ifosfamide Vincristine, doxorubicin; docetaxel, gemcitabine; ifosfamide Ifosfamide, doxorubicin, vincristine, etoposide Multi-agent (detail N/A) Ifosfamide
11
Current case
38
Lung, liver, bone, peritoneum
Vincristine, adriamycin, ifosfamide, cyclophosphamide, etoposide Cyclophosphamide, doxorubicin, etoposide
Abbreviations: CT ¼ computed tomography; MRI ¼ magnetic resonance imaging; N/A ¼ Not available.
Clinical Genitourinary Cancer Month 2017
Radiation Surgery
Survival, mos
Stage
Yes
Yes
N/A
Yes
Yes
2
T2b NX MX Pathologic Unknown
N/A N/A
N/A N/A
N/A N/A
NA T2b NX MX CT
No No
Yes No
10 N/A
T2b NX M1 MRI NA/Unknown
No
No
N/A
T2b NX MX MRI
No No
Yes No
12 4
T2b NX M1 MRI NA/Unknown
Yes
No
24
T2b NX MX CT
No
Yes
14
T2b NX M1 CT
Ali Kord Valeshabad et al 10 cases with PNET of the prostate, round small cells that stained positively for CD99 (MIC-2) were confirmed on histology and immunohistochemistry studies, although there was variable demonstration of Homer-Wright Rosette structure, neuron-specific enolase, vimentin, synaptophysin, and cytokeratin across all studies. Five studies performed molecular studies (either fluorescent in situ hybridization or real-time polymerase chain reaction) searching for the ES/PNET translocation.6-8,11,12 Four of 5 of these reports demonstrated the ES/PNET translocation.6-8,11 Our case was similar to these studies in that there was translocation t(11;22)(q24;q12), small cells that stained positively for CD99, and presence of Homer-Wright Rosettes. However, immunohistochemistry did not demonstrate staining for synaptophysin, neuron-specific enolase, and vimentin. The histologic findings, immunohistochemistry, and molecular real-time polymerase chain reaction studies together confirm PNET disease belonging to the Ewing family of tumors.
Staging Currently, the staging of PNET/ES is based on TNM staging systems for primary tumors of both bone and soft tissue available from the American Joint Committee on Cancer/Union for International Cancer Control, but no widely accepted system exists specifically for the Ewing family of tumors (EFT). However, the American Joint Committee on Cancer/Union for International Cancer Control and the College of American Pathologists currently use the TNM staging system for soft tissue sarcomas for extraosseous ES.15 Based on our review, all 6 cases with known pathologic results demonstrated stage T2b of PNET of the prostate, defined as having a tumor > 5 cm in the largest dimension in the deep tissue. Four of the 10 cases demonstrated findings suspicious for metastases. The pathologic staging in the other 4 cases could not be determined from the reports alone.
Treatment and Outcome Treatment for EFTs involves a combination of systemic chemotherapy, radiation therapy, and surgical resection. A multimodal treatment strategy was used in all previous 10 cases of PNET of the prostate. Nine of the 10 cases utilized neoadjuvant or adjuvant chemotherapy (one of the reports did not detail their treatment).4,6-12,14 Four of 8 patients underwent surgical treatment with radical prostatectomy,7,8,11,14 and 3 of them underwent radiation therapy.4,7,11 Chemotherapy medications in previous studies included a combination of ifosfamide, etoposide, vincristine, adriamycin, doxorubicin, actinomycin, docetaxel, gemcitabine, and cyclophosphamide. The longest reported survival was 24 months after initial diagnosis by Liao et al.4 The patient in that study had imaging stage of T2b NX M0, the positron emission tomography scan demonstrated no distant metastases, and the patient received vincristine, adriamycin, cylcophosphamide, ifosfamide, and etoposide with radiation therapy. The patient in our study presented with late-stage metastatic disease and underwent chemotherapy with
cyclophosphamide, doxorubicin, and etoposide. The chemotherapy was effective, resulting in almost complete resolution of the lung metastases, and marked improvement in hepatic and bone metastases. The pelvic tumor was found to be smaller in size. After 6 rounds of chemotherapy, our patient underwent surgical pelvic exenteration, but subsequently developed sepsis and ultimately expired after hemodynamic deterioration. There is no established chemotherapeutic regimen for EFTs, particularly PNET of the prostate, and a specific regimen that may influence response to treatment remains to be investigated.
Conclusion In summary, an extremely rare case of metastatic PNET of the prostate is described in this case report. PNET of the prostate involves young male adults, may present as metastatic disease, and has poor outcomes with a survival of less than 1 year despite multimodal treatment strategy with the combination of chemotherapy, radiotherapy, and surgical resection.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Iwamoto Y. Diagnosis and treatment of Ewing’s sarcoma. Jpn J Clin Oncol 2007; 37:79-89. 2. Dutta D, Shivaprasad KS, Das RN, Ghosh S, Chowdhury S. Primitive neuroectodermal tumor of adrenal: clinical presentation and outcomes. J Cancer Res Ther 2013; 9:709-11. 3. Lam CJ, Shayegan B. Complete resection of a primitive neuroectodermal tumour arising in the bladder of a 31-year-old female after neoadjuvant chemotherapy. Can Urol Assoc J 2016; 10:E264-7. 4. Liao C, Wu X, Wang X, Li H. Primitive neuroectodermal tumor of the prostate: case report from China. J Cancer Res Ther 2015; 11:668. 5. Parakh R, Parakh S, Tretiakova M. Primitive neuroectodermal tumor and Wegener’s granulomatosis of the kidney: a curious combination of two rare entities. Case Rep Urol 2017; 2017:1750694. 6. Al Haddabi I, Al Bahri M, Burney I. Cytokeratin-positive primitive neuroectodermal tumor of the prostate: case report and review of literature. Indian J Pathol Microbiol 2012; 55:569-71. 7. Colecchia M, Dagrada G, Poliani PL, Messina A, Pilotti S. Primary primitive peripheral neuroectodermal tumor of the prostate. Immunophenotypic and molecular study of a case. Arch Pathol Lab Med 2003; 127:e190-3. 8. Funahashi Y, Yoshino Y, Hattori R. Ewing’s sarcoma/primitive neuroectodermal tumor of the prostate. Int J Urol 2009; 16:769. 9. Kumar V, Khurana N, Rathi AK, et al. Primitive neuroectodermal tumor of prostate. Indian J Pathol Microbiol 2008; 51:386-8. 10. Mohsin R, Hashmi A, Mubarak M, et al. Primitive neuroectodermal tumor/Ewing’s sarcoma in adult uro-oncology: A case series from a developing country. Urol Ann 2011; 3:103-7. 11. Peyromaure M, Vieillefond A, Boucher E, et al. Primitive neuroectodermal tumor of the prostate. J Urol 2003; 170:182-3. 12. Shibuya T, Mori K, Sumino Y, Sato F, Mimata H. Rapidly progressive primitive neuroectodermal tumor of the prostate: a case report and review of the literature. Oncol Lett 2015; 9:634-6. 13. Thete N, Rastogi D, Arya S, et al. Primitive neuroectodermal tumour of the prostate gland: ultrasound and MRI findings. Br J Radiol 2007; 80:e180-3. 14. Wu T, Jin T, Luo D, Chen L, Li X. Ewing’s sarcoma/primitive neuroectodermal tumour of the prostate: a case report and literature review. Can Urol Assoc J 2013; 7:E458-9. 15. Carpentieri DF, Bowen J, Krausz T, Qualman SJ, Rubin BP, Hill DA. Protocol for the examination of specimens from patients with primitive neuroectodermal tumor (PNET)/Ewing sarcoma (ES) 2012, Available at: http://www.cap.org/Show Property?nodePath¼/UCMCon/Contribution%20Folders/WebContent/pdf/pnet ewing-12protocol.pdf. Accessed: October 16, 2017.
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