Primary desmoplastic small round cell tumour of the prostate

Abstract

Desmoplastic small round cell tumour (DSRCT) is a highly aggressive soft-tissue sarcoma with distinctive morphological features and characteristic EWSR1::WT1 gene fusion. DSRCT occurs in a variety of anatomic sites, with abdominal cavity being the most common location. Primary DSRCTs arising in the male genital system are exceedingly rare, with no documented definitive cases of primary DSRCT of the prostate to date, although 28 cases of DSRCT in the testicular or paratesticular regions have been reported. We here present two cases of primary DSRCT of the prostate. Both cases demonstrated the distinct morphology and the typical multiphenotypic immunohistochemical profile, and the characteristic EWSR1::WT1 fusion verified by fluorescent in situ hybridisation. Our cases expand the anatomic distribution of primary DSRCT and highlight the importance of considering this rare tumour in the differential diagnoses of small cell malignancies of the prostate.

Background

Desmoplastic small round cell tumour (DSRCT) is a highly aggressive soft-tissue sarcoma that primarily affects children and young adults, with a striking male predominance.¹ It was first described by Gerald and Rosai in 1989, who demonstrated the characteristic, diverse phenotypic differentiation of DSRCT based on morphological and immunohistochemical studies.²

Histologically, DSRCT is characterised by well-demarcated nests of small round or oval cells in prominent desmoplastic stroma. Immunohistochemically, DSRCT typically shows multiphenotypic differentiation, expressing various epithelial, mesenchymal and neural markers, such as cytokeratins, epithelial membrane antigen (EMA), desmin and neuron-specific enolase (NSE).³

Genetically, DSRCT is characterised by recurrent chromosomal translocation t (11; 22) (p13; q12), resulting in in-frame fusion of the first 7 exons of EWSR1 (22q12.2) gene with exons 8–10 of WT1 (11p13) gene.¹ The EWSR1::WT1 fusion is considered to be a specific diagnostic molecular change for DSRCT, which can be readily demonstrated by fluorescence in situ hybridisation (FISH) or next-generation sequencing.

The abdominal cavity is the most common location for DSRCTs. Primary cases outside the abdominal cavity are much rarer, but have been described in a variety of anatomic locations, including the thoracic cavity, the head and neck region, and even rarer sites such as the limbs, ovary, the pancreas and the brain.4,6

In the genitourinary system, 17 primary DSRCTs have been reported in the kidney, 28 in the testicular and paratesticular region and 18 in the ovary.6,9 Several cases have been reported in the urinary bladder and the uterus. Although earlier reports mentioned a couple of pelvic cases with apparent periprostatic or prostate involvement, no definitive cases of primary prostate or seminal vesicle cases have been reported.^{10 11}

We herein report two cases of primary DSRCTs of the prostate (both clinically suspected as advanced-stage prostate carcinoma) with the typical morphological and immunohistochemical features of DSRCT and the characteristic EWSR1::WT1 fusion confirmed by FISH.

Clinical presentation

Case 1 was a 33-year-old man who presented with urinary frequency and dysuria for 5 months. Enhanced MRI revealed a 5.5 cm×5.0 cm×4.5 cm homogeneous mass in the prostate, which occupied almost the entire prostate and invaded into bilateral seminal vesicle glands and the posterior wall of the bladder (figure 1A­­­­­–C), as well as suspected pelvic lymph node metastases. Systematic physical examination and imaging studies revealed no additional findings in other organ systems. Prostate adenocarcinoma was considered by clinical and imaging studies and robot-assisted laparoscopic radical prostatectomy and cystectomy together with pelvic lymph nodes resection were performed.

Figure 1. The enhanced MRI of case 1 revealed an enlarged homogeneous mass in the prostate that had invaded the bilateral seminal vesicle glands as well as the posterior wall (arrows) of the bladder (A–C).

Case 2 was a 44-year-old man who presented with urinary frequency and urgency for 8 months. Enhanced abdominal CT revealed the prostate tumour mass with the largest diameter being 10.0 cm. The tumour invaded the posterior bladder wall, the right ureteral bladder entrance, the seminal vesicles and the anterior wall of the rectum, with multiple enlarged lymph nodes in the right inguinal area (figure 2A,B). The largest lymph node was located on the left side of the rectum, about 5.1 cm×4.0 cm in size. Systematic clinical examinations revealed pitting oedema in both lower extremities and the enlarged lymph nodes were palpable in the right inguinal area. The clinical and imaging diagnosis was prostate carcinoma, and needle biopsies were performed.

Figure 2. The enhanced CT scan of case 2 revealed a large heterogeneously enhancing tumour (yellow star) of the prostate (A). The tumour invaded the posterior wall of the bladder and occupied the right ureteral bladder entrance (yellow arrows). The tumour invaded the rectum (yellow arrow), and an enlarged lymph node, approximately 5.0 cm in diameter, was observed (yellow circle) (B).

Pathological findings

Grossly, the tumour from case 1 was poorly circumscribed (5.0 cm×5.0 cm×4.0 cm), with suspected invasion of the bladder and bilateral seminal vesicle glands. Three enlarged iliac vascular lymph nodes were sectioned, with the maximum diameter ranging from 1.3 cm to 5.8 cm. Microscopically, the tumour was composed of small round blue tumour cells arranged in well-defined nests and separated by markedly desmoplastic stroma (figure 3A). The tumour cells also invaded between prostate glands (figure 3B). Necrosis and perineural invasion were readily observed (figure 3C). The tumour cells were uniform, small sized, with sparse cytoplasm, indistinct cell border and hyperchromatic nuclei with inconspicuous nucleoli (figure 3D). Mitoses were numerous (10–15/2 mm²). The tumour invaded the bladder wall (figure 3E). Metastases were detected in two of three resected iliac lymph nodes (figure 3F).

Figure 3. The morphological features of desmoplastic small round cell tumour (DSRCT). (A) The tumour cells were arranged in well-defined nests, separated by markedly desmoplastic stroma (40×, case 1). (B) The tumour displayed invasive extension, with normal prostate glands adjacent to the tumour cells (200×, case 1). (C) Perineural invasion was commonly observed (100×, case 1). (D) The tumour cells appeared uniform, small sized, with sparse cytoplasm, blurred cell borders, and hyperchromatic nuclei with invisible nucleoli (400×, case 1). (E) Involvement of the bladder wall was evident (100×, case 1). (F) Tumour metastasis to iliac vascular lymph nodes was evident (40×, case 1). (G) The tumour cells were irregular sheet-like, surrounded by proliferative fibrous stroma (20×, case 2). (H) The tumour cells were small, round or elongated, with scant cytoplasm and unclear cell boundaries (400×, case 2).

In case 2, the tumour cells exhibited similar morphological features with irregular nested or sheet-like invasive growth pattern (figure 3G,H). In the limited biopsy material, mitosis was scarce (0–1/2 mm²).

Tumour cells of both cases showed typical multiphenotypic immunohistochemical staining pattern, with variegated positivity for desmin (figure 4A), pancytokeratin (often dot-like) (figure 4B), CD99 (figure 4C), NSE (figure 4D), EMA (focal) and S100. The tumour cells were uniformly negative for NKX2.2, NKX3.1, MyoD-1, CgA, Syn, P63 and ERG.

Figure 4. The immunohistochemical results of both cases demonstrated a diffuse paranuclear staining pattern with desmin (400×) (A), dot-like positivity of pancytokeratin (PCK) (400×) (B), and diffuse cytoplasmic membrane positivity with CD99 and neuron-specific enolase (NSE) (400×) (C, D).

Molecular studies

FISH assays for EWSR1::WT1 gene fusion were performed by using dual-colour DNA fusion probes (Anbiping Pharmaceutical Technology Co., Guangzhou, China). EWSR1::WT1 gene fusion was identified in both cases (figure 5A,B).

Figure 5. Fluorescence in situ hybridisation (FISH) with an EWSR1-WT1 fusion probe detected more than 10% of EWSR1::WT1 gene fusion of case 1 (A) and case 2 (B). WT1 and EWSR1 gene loci were represented by red and green signals, respectively, and fusion was represented by red–green fused signals (yellow).

Treatment and follow-up

The patient of case 1 received postoperative chemotherapy consisting of vincristine (2 mg), actinomycin D (2.5 mg) and cyclophosphamide (2000 mg) for 12 cycles, followed by radiotherapy (66 Gy in 2.2 Gy per session over 30 sessions) (66 Gy/2.2 Gy/30 F) for one cycle. The patient has been followed by regular clinical check-up and enhanced abdominal CT scans at 3–7 month intervals, There was no evidence of local recurrence or distant metastasis thus far. The patient of case 2 received adjuvant chemotherapy after definitive diagnosis for two cycles, which included vincristine (2 mg), doxorubicin (120 mg) and cyclophosphamide (2000 mg). The patient has been followed for 3 months by clinical check-up and an enhanced abdominal CT scan, with no evidence of distant metastasis whereas significant reduction in sizes of the prostate tumour mass and the enlarged lymph nodes was noted.

Discussion

DSRCT is a unique mesenchymal neoplasm characterised by distinct histological features often exhibiting multiphenotypic differentiation.¹ It is a highly aggressive soft-tissue sarcoma that predominantly affects adolescent males, with a peak incidence between 20 and 30 years. This tumour typically arises in the abdominal and pelvic cavities with no specific clinical symptoms.¹² The most common imaging finding of DSRCT is heterogeneous soft-tissue masses in the abdomen and pelvis without an obvious organ of origin.³ Instances outside abdominal cavity are rare, with cases reported in various locations such as the thoracic cavity, paratesticular region, intracranial region, head and neck (including salivary glands), ovary, pancreas, limbs and brain.

Primary DSRCTs of the genitourinary system are extremely rare, with only 28 reported cases affecting the testis and paratesticular region (such as the epididymis and scrotum), 17 cases of the kidney, 18 cases of the ovaries, 3 cases of the uterus and 1 case in the urinary bladder (table 1, online supplemental table 1). Earlier reports on abdominal and pelvic case series mentioned a few cases involving the prostate/periprostatic area,^{12 13} but bona fide DSRCT presenting as a primary prostate lesion with molecular confirmation has not been described.^{12 13}

Table 1. Literature review of DSRCT in the genitourinary system.

Sites	N	Age range (year)	M:F	EWSR1::WT1 fusion	Recurrence or metastasis	Follow-up	Year	Author
Testis/paratesticular region	28	13–65	28: 0	100% (9/9)	38% (8/21)	20 cases with available follow-up: NED (11/20); AWD (2/20); DOD (7/20)	2021	Reviewed by Romagnol et al8
Kidney	17	6–41	8: 8 (one patient N/A)	100% (13/13)	24% (4/17)	12 cases with available follow-up: NED (5/12); AWD (4/12); DOD (3/12)	2020	Galliani et al7
Ovary	18	6–30	0: 18	71% (5/7)	N/A	14 cases with available follow-up: alive (5/14); dead (9/14)	2020	Reviewed by Vujić et al6
							2019	Atef et al9
Uterus	3	46–49	0: 3	100% (2/2)	100% (1/1)	1 case with available follow-up: NED	2022	Dundr et al11
							2018	Al-Ibraheemi et al19
							2017	Arshad et al20
Bladder	1	22	1: 0	N/A	100% (1/1)	DOD	2010	Diao et al10
Ureter	0	–	–	–	–	–	–	–
Prostate involvement	2	17–32	2: 0	N/A	N/A	DOD	1997	Furman et al13
							1993	Ordóñez et al12
Periprostatic region	3	24–32	3: 0	N/A	N/A	DOD	1997	Furman et al13
							1993	Ordóñez et al12
Prostate	2	33–44	2: 0	100% (2/2)	–	NED	2024	Present study

AWD, alive with disease; DOD, dead of diseaseF, female; M, male; N, number of cases; N/Anot availableNED, no evidence of disease

The present two cases presented with predominantly urinary symptoms such as urinary frequency, dysuria, urgency and increased nocturia, without any other abdominal, pelvic or peritoneal symptoms or signs. Imaging examinations revealed that the primary tumours were centred in the prostate, while no other pelvic or abdominal lesions were detected. One case exhibited local lymph node metastasis and direct invasion of the bladder wall, whereas the other case displayed direct invasion of adjacent organs. The diagnoses were confirmed by typical morphological, immunohistochemical features and the characteristic EWSR1::WT1 fusion. These cases of primary DSRCT originating from the prostate broaden the anatomic distribution of this rare tumour, which should alert the pathologists to include DSRCT in the differential diagnosis of poorly differentiated or small round cell tumours of the prostate.

DSRCT poses several challenges in differential diagnosis due to its resemblance to various malignancies with small round cell morphology, notably Ewing’s sarcoma (EWS), alveolar rhabdomyosarcoma (ARMS) and synovial sarcoma.³ EWS typically lacks the expression of epithelial and mesenchymal markers but exhibits strong positivity for CD99 and NKX2.2 immunohistochemically, and characteristic gene rearrangements of EWSR1::FLI1 or EWSR1::ERG or other ETS family genes, or gene fusion involving FUS and ETS family members, but not EWSR1::WT1 fusion. It is important to notice that the EWRS1 break apart probe alone could not differentiate between DSRCT and EWS, or EWRS1-non-ETS fusion sarcomas, and the respective fusion partners must be identified for definitive diagnosis. ARMS shares some histological similarities with DSRCT but is featured by myoblasts of varied sizes and shapes. Myogenic markers (MyoD-1, myogenin) are positive, but AE1/AE3 and NSE are negative. ARMS is characterised by the recurrent translocation involving PAX3/7 and FOXO1. Synovial sarcoma is commonly found near large joints in the extremities, characterised by the SYT::SSX fusion (t (X; 18) (p11; q11)).

Recently, the EWSR1::WT1 fusion has been identified in several cases of sarcomas considered to be distinct from classic DSRCT, based on morphological features (such as a spindle cell or epithelioid component, glomus tumour-like morphology, and myxoid or oedematous stroma) and genomic analysis (DNA copy number variations or differentially expressed genes), as well as apparent indolent behaviour.^{14 15} Interestingly, the three cases reported in one study still clustered with classic DSRCT based on DNA methylation profiles, but showed significant DNA copy number variation profiles distinct from classic DSRCT.¹⁵ Whether these EWSR1::WT1 fusion sarcomas represent novel, distinct entities, and whether EWSR1::WT1 fusion also occurs in other yet unknown tumour types, are questions eagerly awaiting future studies.

The EWSR1::WT1 chimeric transcription factor in DSRCT consists of the aminoterminal domain (NTD) (with potent transcriptional activation activity) from the EWS gene, and a DNA-binding domain (zinc fingers 2 to 4) from the WT gene.¹ It has been shown that fusion proteins resulting from gene fusion of EWSR1 with various partners possessed abnormal transcriptional activities and participated in abnormalities involving diverse epigenetic mechanisms (including DNA methylation, histone modification and non-coding RNAs).¹⁶ Recent studies have demonstrated that the EWSR1::WT1 oncoprotein is essential to DSRCT growth in vivo and in vitro by transcriptionally activating a variety of target genes, notably several cell cycle genes controlling G1/S or G2/M transitions.^{17 18} WT1 has two isoforms generated by alternative splicing that include or exclude three amino acids (Lys, Thr and Ser, termed KTS) between WT1 zinc fingers 3 and 4, designated as E+KTS and E-KTS, respectively.¹⁷ They show different DNA binding specificities and transcriptional activities. The EWS::WT1 chimaera leads to transcriptional upregulation and stimulates cell-cycle progression over the cyclin D-CDK4/6-RB checkpoint through the binding of the E-KTS isoform to the CCND1 promoter.¹⁷

DSRCT is highly aggressive and has a poor prognosis. The estimated 5-year overall survival rate is only 10%–15%. Although the two patients in the present report have not yet shown tumour progression, longer follow-up is needed to fully assess the outcome. The treatment of DSRCT remains challenging. The conventional treatment for DSRCT includes surgical resection, chemotherapy and radiation therapy.¹⁷ Other treatment methods such as high-dose alkylating agent chemotherapy and trial complete cytoreductive surgery have been used.⁶ Recent research indicated that CDK4/6 inhibitors may serve for targeted therapy of DSRCT.¹⁷

In summary, the current report presented two cases of primary DSRCTs of the prostate, underscoring the importance of considering this rare tumour in the differential diagnoses for small-cell malignancies of the prostate.