Pathology of Prostatic Stromal Sarcoma

Prostatic stromal sarcoma is a rare malignant neoplasm of mesenchymal origin that is believed to originate from specialized stromal prostatic cells. ^{[1, 2, 3, 4, 5]} There is debate on its specific definition, pathology, and prognosis. ^{[3, 6]}

This tumor was initially named as atypical stromal hyperplasia, cystosarcoma phyllodes, prostatic cystic epithelial-stromal tumor, and mullerian adenosarcomalike tumor; most of these were presented as a few isolated case reports and without distinction from other spindle cell neoplasms of the prostate. ^{[1, 7, 8]} The phyllodes pattern of mesenchymal proliferation has been included with stromal tumors of uncertain malignant potential (STUMP). ^{[9, 10, 11, 12, 13]}

Prostatic stromal sarcoma was formally described by Gaudin et al in 1998. ^[1] The World Health Organization (WHO) (also known as l'Organisation Mondiale de la Sante [OMS]) classification of prostatic stromal proliferations includes this tumor as a distinctive spindle cell neoplasm and categorizes them as STUMPs and stromal sarcomas. ^[14] (See the related images below.)

Pathology of prostatic stromal sarcoma. Medium magnification showing spindle cell sarcoma replacing and distorting prostatic tissue. Note the presence of hypercellularity and nuclear atypia. The residual prostatic gland in the center shows no anaplasia.

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Pathology of prostatic stromal sarcoma. At higher magnification of the previous image, numerous mitoses can be seen. The tumor shows no specific pattern of differentiation.

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Pathology of prostatic stromal sarcoma. This image demonstrates a malignant spindle cell tumor replacing the prostatic stroma and invading vascular structures. The normal fibromuscular stroma of the prostate is appreciated at the right side of the figure.

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The true incidence of prostatic stromal sarcomas has not been established because of the rarity of this tumor. ^{[1, 2, 3, 4, 14, 15, 16, 17, 18, 19, 20]}  However, it is estimated to account for 0.1% of all prostate malignancies. ^{[21, 22, 23, 24]}

In the largest series, patients' ages ranged from 25 to 86 years, and at least half of these patients were younger than 50 years. ^{[1, 3, 4, 14]} There have also been reported cases in younger adults. ^{[15, 16]}

Sarcomas arising in the prostatic stroma in children are virtually always rhabdomyosarcomas. ^{[25, 26]} Some authors consider stromal tumors of uncertain malignant potential (STUMPs) and stromal sarcoma to be in a spectrum of the same disease, ^{[3, 4]} whereas others favor STUMP as a type of hyperplasia with little to no malignant potential. In contrast to STUMPs, stromal sarcomas tend to affect a slightly younger population. ^[4]

The prostate has a complex stromal-epithelial interaction that responds to hormonal stimulation that is responsible for prostatic epithelial morphogenesis, differentiation, proliferation, and expression of prostate-specific proteins. It is believed anomalous or exaggerated stimulation in these pathways may give origin to stromal sarcoma. ^[27]

Stromal sarcoma may arise de novo or coexist with either preexistent or concurrent prostatic stromal tumors of uncertain malignant potential (STUMP), suggesting a potential for STUMP in dedifferentiate into stromal sarcoma. Indeed, Herawi et al studied 50 stromal tumors of prostate and found 14 stromal sarcomas, of which 7 were associated with STUMP. ^[2]

There is no specific site of occurrence of stromal sarcoma within the prostate. However, these tumors have been reported to arise more often from the posterior region of the prostate, and some extend to the vasa deferentia and seminal vesicles. ^{[17, 28, 29]} Some large tumors may protrude outside the prostate and mimic gastrointestinal stromal tumors or other neoplasms arising outside the prostate.

Common clinical presentations in men with prostatic stromal sarcoma are urinary retention, abnormal digital rectal examination (DRE), hematuria or hematospermia, and a palpable rectal mass. Although serum prostate-specific antigen (PSA) is usually negative, interestingly, there are also some reported cases with either sole or concurrent elevation in serum PSA. ^{[1, 3, 18, 19, 30]}

There are some reports of combined stromal sarcoma with prostatic adenocarcinomas; however, it is likely that these represent sarcomatoid carcinomas (carcinosarcomas) rather than true primary sarcomas colliding with prostatic carcinomas. ^[18] Although there have been reported cases, sarcomatoid carcinomas of the prostate are more likely to occur than two separate colliding tumors.

There is no specific gross finding in prostatic stromal sarcomas. These tumors can be solid or mixed with cystic areas, and they may show a tan to white cut surface and areas of edema and hemorrhage. Necrosis may also be found, especially in high-grade tumors. ^{[4, 30]}

Size is variable and has ranged from 2 to 18 cm in the hitherto reported cases. Interestingly, size has not correlated with the grade or clinical behavior of the tumor in most cases. ^{[2, 3, 4]}

Stromal sarcomas (see the images below) are histologically characterized by stromal overgrowth, variable cellular atypia, mitosis, and increased cellularity (see the images below). They are further divided into low-grade and high-grade tumors, based on moderate to high cellular atypia and hypercellularity in high-grade tumors. Other findings such as necrosis and high mitotic counts are more commonly found in high-grade neoplasms. ^{[18, 19, 31]}

Pathology of prostatic stromal sarcoma. Medium magnification showing spindle cell sarcoma replacing and distorting prostatic tissue. Note the presence of hypercellularity and nuclear atypia. The residual prostatic gland in the center shows no anaplasia.

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Pathology of prostatic stromal sarcoma. At higher magnification of the previous image, numerous mitoses can be seen. The tumor shows no specific pattern of differentiation.

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The stromal component can be solid or interspaced with normal glandular elements (see the images below). The most common patters are the storiform, epithelioid, fibrosarcomatous, or "patternless-type." ^[4] Leaflike structures, resembling breast phyllodes tumors, are also found. These are more associated with low-grade sarcomas, and on histologic grounds alone, it may be difficult to predict the behavior of such tumors because of their bland appearance. The distinction between low-grade prostatic stromal sarcomas and stromal tumors of uncertain malignant potential (STUMPs) is based on the degree of cytologic atypia, and they are supported by the local aggressive behavior found in low-grade sarcomas. ^{[1, 3]}

Pathology of prostatic stromal sarcoma. This image demonstrates a malignant spindle cell tumor replacing the prostatic stroma and invading vascular structures. The normal fibromuscular stroma of the prostate is appreciated at the right side of the figure.

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Pathology of prostatic stromal sarcoma. Medium magnification showing round to spindle cells. There is hypercellularity, focal myxoid change, and cytologic atypia present.

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Pathology of prostatic stromal sarcoma. High magnification of high-grade sarcoma with severe anaplasia, atypical mitoses, and a nondistinct histologic pattern. This case was focally positive for CD34 and progesterone receptor.

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STUMPs may also be misidentified as prostatic hyperplasia owing to certain similarities in histologic and clinical features. ^[32] A 2016 retrospective study (2009-2014) that evaluated 702 consecutive pathology slides with a diagnosis of prostatic hyperplasia found that 3 cases (0.43%) were histologically misdiagnosed as prostatic hyperplasia instead of STUMP, in which there was hypercellular stroma, infiltrating between the hyperplastic glands, as well as cells showing some degree of pleomorphism, nuclei with vesicular chromatin, and few mitotic figures. ^[32]

As a neoplasm originating from specialized prostatic stroma, stromal sarcomas are progesterone-receptor (PR) positive, normally in a diffuse pattern. Occasional cases have shown estrogen-receptor (ER) positivity. CD34 and vimentin are both expressed diffusely in most cases. Smooth muscle actin (SMA) is reportedly positive in some stromal tumors of uncertain malignant potential (STUMPs) but not in stromal sarcomas. Variable activity is also reported for prostatic-specific antigen (PSA), cytokeratin [CK] adverse event 1/3 (AE1/AE3), and Papanicolaou (PAP) stain, whereas it is negative for S100, CD117, and thyroid transcription factor 1 (TTF-1). ^[13]

Rare desmin positivity is found in a minority of the cases. Beta-catenin and p53 expression are more commonly found in high-grade sarcomas, but they are also occasionally expressed in low-grade neoplasms. ^[4]  A high Ki-67 index is seen in most high-grade cases, but this finding is of little utility in the diagnosis of these neoplasms.

The current literature provides very little data about specific molecular or genetic abnormalities in prostatic stromal sarcoma ^{[13, 33]} ; neither are there studies that show any specific alteration that could predict the development of a stromal sarcoma from a stromal tumor of uncertain malignant potential (STUMP). However, in a study that used array comparative genomic hybridization to evaluate chromosomal aberrations in specialized prostatic stromal tumors, Pan and Epstein reported anomalies in four cases of stromal sarcomas and seven of eight cases of STUMP, with the most common alterations being losses of chromosome 13 (10 cases), chromosome 14 (9 cases), and chromosome 10 (7 cases). ^[33] The  stromal sarcomas and STUMPs shared similar profiles of chromosomal imbalances.

Low-grade sarcomas are locally aggressive neoplasms that can show contiguous involvement of seminal vesicles and extraprostatic extension. They normally do not metastasize or involve the bladder and rectum, ^{[1, 4]} but the true clinical behavior of these neoplasms is not entirely known, as only a few cases have been reported. It has been suggested that even low-grade sarcomas can locally invade, despite at times having a relatively bland cytology. ^[4]

However, high-grade neoplasms are more aggressive, with a higher prevalence of spread to the seminal vesicles, bladder, and rectum. Surgical margins are sometimes difficult to obtain because of the involvement of adjacent structures. Vascular invasion has also been shown to be present in high-grade sarcomas, with selected cases demonstrating metastases to the liver and lung. ^{[2, 19, 34]}

Although there is no specific staging system for prostatic stromal sarcoma, pathologists should document the status of margins, distance to the closest margin, involvement of the seminal vesicles, and extraprostatic extension, similar to what is performed in adenocarcinomas. This process will provide clinicians with necessary information.

Because prostatic stromal sarcoma is a rare tumor, there are limited data about its prognosis, mostly in a very few case reports or from series with a small number of cases. In general, the prognosis is poor. ^{[21, 23, 24, 35]} Low-grade stromal sarcomas can be locally invasive, but these tumors normally do not metastasize. Nonetheless, locally advanced tumors have poor local control and overall survival,with a high risk of recurrence. ^{[24, 35]}

Primary prostatic sarcomas and high-grade tumors are more aggressive and may lead to death mainly because of metastasis or early local invasion. A minority of patients diagnosed with high-grade stromal sarcomas showed poor short-term survival if they were diagnosed early with resection with clear margins. Cases with distant metastasis behaved variably, with some early deaths due to widespread metastases and others showing long-term survival years after their initial presentation. ^{[17, 18]}

Patients are normally treated with radical prostatectomy or cystoprostatectomy. Although there are few data to evaluate the effectiveness of chemotherapy or radiotherapy, ^{[1, 2, 19, 28]} primary prostatic sarcomas are typically aggressive and require multimodal treatment with surgery, (neo)adjuvant radiation, and/or chemotherapy. ^[24] Radiotherapy appears to improve 5-year local control and overall survival in surgically treated patients. ^[35]