Clinical History
49 year old male presenting a 8 cm mass in the ileum.
Case 5 - Figure 3 - Focally, a hemangiopericytoma-like vascular pattern is observed
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Case 5 - Figure 4 - In some areas the presence of eosinophilic intercellular collagen becomes evident
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Pathologic findings
The lesion is composed of a uniform spindle cell proliferation, focally featuring an
hemangiopericytoma-like vascular pattern. Immunostains showed strong positivity for EMA and vimentin.
Cytokeratin was focally positive while smooth muscle actin, CD34, KIT (CD117) and S-100 were all
negative. FISH analysis revealed rearrangement of the SYT gene.
Diagnosis: Primary monophasic spindle cell synovial sarcoma of ileum.
Discussion:
Synovial sarcoma (SS) is a mesenchymal malignancy that accounts for approximately 10% of all soft
tissue sarcomas [1]. Clinically it tends to occur in the lower limbs of young adults, with a peak
incidence ranging between the first and the third decades. A less frequent but well-characterized site
of occurrence is the head and neck region, followed by the mediastinum. Recently SS has been reported in
unusual anatomic locations such as the abdominal cavity, the larynx and hypopharynx and even the heart
[2,
3]
, making of molecular genetics an important diagnostic adjunct [4].
Microscopically, two main variants of SS are recognized: the monophasic and the biphasic subtypes.
Both variants feature a spindle cell population set in a variable collagenous background and associated
with a hemangiopericytoma (HPC)-like vascular pattern (i.e. a vascular network composed of branching and
dilated thin-walled blood vessels). In the biphasic subtype, glandular-like structures are also found.
In many circumstances, gland formation can be very subtle and represented merely by the clustering of
cuboidal cells that are more easily identified by means of both reticulin stains and
immunohistochemistry. The existence of a predominantly monophasic epithelial pattern has been also
reported.
In approximately 20% of cases, SS exhibits an undifferentiated, high grade morphology and are usually
indicated as "poorly differentiated SS (PDSS)" [5]. Three main groups of PDSS can be identified: a
first group exhibiting a round cell morphology associated with necrosis as well as high mitotic count; a
second group characterized by the presence of larger cells, exhibiting polygonal cytoplasm that can
rarely feature a rhabdoid morphology; and a third group represented by a high-grade spindle cell tumor
often featuring a "herringbone" growth pattern.
The differential diagnosis of round cell PDSS includes all round cell sarcomas (ES/PNET, DSRCT, and
ARMS) as well as non-sarcomatous round cell neoplasm, such as Merkel cell carcinoma (MCC). If PDSS
exhibits a polygonal, large cell morphology the differential diagnosis will include epithelioid sarcoma
(in particular the proximal type), extrarenal rhabdoid tumor, and undifferentiated carcinoma. The
high-grade spindle cell variant should be distinguished from malignant peripheral nerve sheath tumors
(MPNST) and fibrosarcoma. When dealing with any variants of PDSS extensive sampling is mandatory, as it
frequently reveals the presence of more typical areas.
Of course, ancillary diagnostic techniques play a major role in permitting to arrive at the correct
diagnosis. SS is characterized by a complex and relatively distinctive immunophenotype, which includes
co-expression of mesenchymal (vimentin) and epithelial markers (cytokeratins and EMA). As morphological
features of epithelial differentiation may be very subtle, immunohistochemical stains represent a truly
valuable diagnostic aid. Cytokeratins tend to decorate most biphasic synovial sarcomas; however, when
dealing with the monophasic subtype the percentage of immunopositivity drops to 60% to 70%. It is
important to note that cytokeratin immunoreactivity could not be demonstrated in more than 50% of PDSS
[5] and that high molecular weight cytokeratins have proved more sensitive than low molecular weight
ones. As far as demonstration of epithelial differentiation is concerned, EMA appears to be the most
sensitive marker, as it appears to stain most cases of PDSS, including those which failed to express
cytokeratins.
When dealing with a round cell neoplasm showing expression of epithelial markers, PDSS should always
be included in the differential diagnosis. However, it should be remembered that cytokeratin as well as
EMA immunoreactivity can be observed in up to 20% of ES/PNETs as well as in most DSRCTs. The
differential diagnosis with the ES/PNET group is made even more challenging by the fact that SS can
express CD99 in a percentage of cases ranging between 50% and 100% of cases, depending upon use of heat
induced epitope retrieval techniques
[5,
6]
. Between 30% and 60% of SS express S-100 protein, leading to
potential confusion when dealing with the differential diagnosis between monophasic spindle cell SS and
MPNST [7].
Because of the existence of significant immunophenotypic overlap, in order to avoid diagnostic
pitfalls caused by the use of single reagents, the application of a panel of immunohistochemical markers
is strongly recommended.
Cytogenetically, all SS variants are characterized by the reciprocal translocation
t(X;18)(p11.2;q11.2), which leads at molecular level to fusion between the gene SYT (Synovial sarcoma
Translocation) on chromosome 18 and the genes called SSX1 (Synovial Sarcoma X breakpoint), SSX2 and SSX4
on the X-chromosome
[8,
9,
10]
. The SYT-SSX1 translocation seems to be associated with the biphasic type
[11]. The SYT gene is unrelated to any other known gene but contains a predicted
glutamine-proline-glycine-rich region, suggestive of a transcriptional activation domain. The SSX1, SSX2
and SSX4 genes are also unrelated to other known genes and encode proteins that show a remarkable
homology. As in other sarcoma subtypes, the translocation leads to the formation of a chimeric
transcript. The identification of the target genes of these novel transcription factors represents a
further fundamental step in the comprehension of the molecular pathogenesis of SS [12].
The X;18 translocation has been regarded as highly specific for the diagnosis of SS and consequently
considered as an optimal diagnostic tool; however, this concept was recently challenged by a single group
of investigators who found a t(X;18) in a variety of soft tissue sarcomas, including more than half of
the MPNSTs tested [13]. Subsequently it became evident that those data represented the result of PCR
contamination, raising the necessity of assuring appropriate quality control in molecular procedures, in
particular when applied to clinical practice [14]. Certainly molecular genetics plays an important role
in supporting morphologic diagnosis, in particular when dealing with poorly differentiated SS as well as
with cases arising at unusual anatomic locations. The case presented herein fits perfectly with the
concept of an integrated diagnostic approach. In consideration of the great interest generated by the
advent of targeted therapy, any lesion arising in the GI tract would naturally raise the possibility of a
diagnosis of GIST [15]. KIT negativity "per se" does not exclude such a possibility [16], and even if
both morphology and immunohistochemistry strongly supported a SS, in this context the demonstration of
SYT rearrangement had a high confirmative value.
Molecular analysis has not only been used as an aid to morphological diagnosis but may also provide
important independent prognostic information. Not only does the SYT-SSX2 fusion transcript correlate
with the monophasic phenotype, but it seems to be associated with a significantly better metastasis-free
survival
[11,
17]
. However, data from the French Sarcoma Group have recently contradicted these findings,
reaffirming the role of grading as a main prognostic indicator [18]. The identification of effective
prognostic parameters is one of the greatest challenges of contemporary surgical pathology. Recent data
indicates that tumor size (> 5 cm), presence of neurovascular invasion, p53 overexpression, and high
Ki67 proliferation index identify subsets of SS patients with increased risk of tumor relapse
[19,
20,
21]
.
As already underlined, whether molecular pathology may provide in the future better indicators is still
to be elucidated [22]
The recognition of SS is also of paramount importance to ensure the right therapeutic approach. The
discovery of SS's chemosensitivity to ifosfamide compounds has represented an important clinical advance
in the therapeutic approach to soft tissue sarcomas of the adults
[23,
24]
. In order to ensure a proper
therapeutic approach, the distinction of SS from other mesenchymal malignancies is mandatory. As already
mentioned, the advent of targeted molecular therapies represents a major innovation in the treatment of
neoplastic disease. Data from translational studies using micro-array technology have showed that EGFR
is expressed in synovial sarcomas [25]. This in formation has rapidly led to clinical trials based on
anti EGFR compounds. Recently it has also been shown that approximately two thirds of synovial sarcomas
express ligand-activated KIT and PDGFRβ tyrosine kinase receptors [26], suggesting a possible role
therapeutic for tyrosine kinase inhibitors.
Useful references:
- Fletcher CDM, Martens F, Unni KK. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARCPress, Lyon, 2002.
- Dei Tos AP et al. Synovial sarcoma of the larynx and hypopharynx. Ann Othol Rhinol Laryngol 107:1080-1085, 1998.
- Hazelbag HM, et al. Primary synovial sarcoma of the heart: a cytogenetic and molecular genetic analysis combining RT-PCR and COBRA-FISH of a case with a complex karyotype. Mod Pathol. 17:1434-1439, 2004.
- Coindre JM et al. Should molecular testing be required for diagnosing synovial sarcoma? A prospective study of 204 cases. Cancer 15:2700-2707, 2003.
- Folpe AL et al. Poorly differentiated synovial sarcoma. Immunohistochemical distinction from primitive neuroectodermal tumors and high grade malignant peripheral nerve sheath tumors. Am J Surg Pathol 22:673-682, 1998.
- Dei Tos AP et al. Immunohistochemical demonstration of p30/32MIC2 (CD99) in synovial sarcoma. A potential cause of diagnostic confusion. Appl Immunohistochem 3:168-173, 1995.
- Guillou L et al. S-100 protein reactivity: in synovial sarcomas: A potentially frequent diagnostic pitfall. Immunohistochemical analysis of 100 cases. Appl Immunohistochem 4:167-175, 1996.
- Clark J et al. Identifications of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat Genet 7:502-507, 1994.
- Crew AJ et al. Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J 14:2333-2340, 1995.
- Fligman I et al. Molecular diagnosis of synovial sarcoma and characterization of a variant SYT-SSX2 fusion transcript. Am J Pathol 147:1592-1599, 1995.
- Kawai A et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 338:153-160, 1998.
- Xie Y et al. Gene expression profile by blocking the SYT-SSX fusion gene in synovial sarcoma cells. Identification of XRCC4 as a putative SYT-SSX target gene. Oncogene 22:7628-7631, 2003.
- O'Sullivan MJ et al. Malignant peripheral nerve sheath tumor with (X;18). A pathologic and molecular genetic study. Mod Pathol 13: 1336-1346, 2000.
- Ladany M et al. OnO'Sullivan et al. Mod Pathol 14:733-737, 2001.
- Corless CL et al. Biology of gastrointestinal stromal tumors. J Clin Oncol 22: 3813-3825, 2004.
- Medeiros F et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol 28: 889-894, 2004.
- Ladanyi M et al. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res 62:135-140, 2002.
- Guillou L et al. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J Clin Oncol 22:4040-50, 2004.
- Lewis JJ et al. Synovial sarcoma: A multivariate analysis of prognostic factors in 112 patients with primary localized tumors of the extremity. J Clin Oncol 18:2087-2094, 2000.
- Antonescu C et al. Alterations of cell cycle regulators in localized synovial sarcoma: A multifactorial study with prognostic implications. Am J Pathol 156:977-983, 2000.
- Trassard M et al. Prognostic factors in localized primary synovial sarcoma: a multicenter study of 128 adult patients. J Clin Oncol 15: 19:525-534, 2001.
- Oliveira AM, Fletcher CDM. Molecular prognostication for soft tissue sarcomas: are we ready yet? J Clin Oncol 22 :4031-4040, 2004.
- Connelly EF, Budd GT. Ifosfamide in the treatment of soft tissue sarcomas. Semin Oncol 23 (suppl 6):16-21, 1996.
- Ferrari A et al. Synovial sarcoma: a retrospective analysis of 271 patients of all ages treated at a single institution. Cancer 101:627-34. 2004
- Nielsen TO et al. Tissue microarray validation of epidermal growth factor receptor and SALL2 in synovial sarcoma with comparison to tumors of similar histology. Am J Pathol 2003, 163, 1449-1456.
- Tamborini E et al. Expression of ligand-activated KIT and platelet-derived growth factor receptor beta tyrosine kinase receptors in synovial sarcoma. Clin Cancer Res 10:938-943, 2004.
