—  SPECIALTY CONFERENCE  —

Cytopathology

Case 4 - Synovial Sarcoma

Scott E. Kilpatrick
Women's and Children's Hospital
Chapel Hill, North Carolina


Click on each slide thumbnail image for an enlarged view
Clinical History:
The patient is a 19-year-old man with a soft tissue mass involving the right buttock and lung masses. (Images 4A-4C)

Cytologic Findings:
The smears are highly cellular and composed of mostly individually dispersed and scattered, small cohesive clusters of tumor cells (Image A). The latter appear mostly uniform, round to ovoid with high nuclear to cytoplasmic ratios, round, hyperchromatic nuclei with inconspicuous nucleoli, and scant rims of dense cytoplasm (Images B and C). No bi- or multi-nucleated tumor cells are present. Cell block material reveals similar features but appears more spindled than was perhaps appreciated in the cytologic smears.


Figure 4A - Highly cellular smear composed of individually dispersed and scattered, small cohesive clusters of tumor cells. (Diff-Quik stain, low power)
Figure 4B - Tumor cells appear round to ovoid with high nuclear to cytoplasmic ratios. (Diff-Quik stain, high power)
Figure 4C - Tumors cells have round hyperchromatic nuclei with inconspicuous nucleoli and scant rims of cytoplasm. (Papanicolaou stain, high power)

Immunohistochemistry:
The cells in the cell block material show diffuse and strong membranous positivity for CD99 and focal reactivity for cytokeratin (AE1/AE3). The tumor cells appeared uniformly negative for myogenin, desmin, and S-100 protein.

Cytogenetic analysis:
Conventional cytogenetic analysis revealed the t(X;18) (p11;q11).

Clinical Follow-up:
The patient underwent a resection of the right neck mass that confirmed the cytologic diagnosis of alveolar rhabdomyosarcoma. Additionally, at least 8 of 10 lymph nodes were positive for alveolar rhabdomyosarcoma. Bone scans and CT scans of the chest and abdomen revealed no other evidence of disease. The patient was staged as T1bN1M0, Group III, Stage I, and enrolled on CCG protocol. He is currently doing well, without local recurrence or metastasis at 6 months following the initial diagnosis.

Discussion:
Synovial sarcoma (SS). SS is a soft tissue malignancy of uncertain histogenesis. Based on its morphologic and immunohistochemical properties, it may be more accurately characterized as a "carcinosarcoma" of soft tissues. The original designation of "synovial sarcoma" was based partly on the fact that these tumors frequently arose in soft tissues near, but rarely within, large joints and, histologically, had an epithelial component that was likened to synovium. However, it should be remembered that normal synovium lacks immunoreactivity to keratins. SS typically arises in adolescence and young adults, with a peak incidence between 20 and 40 years of age. The lower extremity is more commonly afflicted than the upper extremity and proximal more often than distal. Radiologically, SS are almost always deeply-seated, presenting as deceptively well-circumscribed but nonspecific soft tissue masses, often containing stippled calcifications.

On the basis of morphologic features, SS may be subtyped into four distinct categories: monophasic fibrous, monophasic epithelial, biphasic, and poorly differentiated.1 The latter categorization likely represents a poorly differentiated form of monophasic fibrous. The monophasic fibrous subtype, according to most recent series, represents the most common variant, followed in decreasing order of frequency by biphasic, poorly differentiated, and monophasic epithelial subtypes.

Cytologic preparations from SS are generally highly cellular and composed of a mostly dyscohesive tumor cell population accompanied by occasional tumor cell aggregates.2 In most cases, individual tumor cells are remarkably uniform with high nuclear to cytoplasmic ratios, round to ovoid hyperchromatic nuclei, inconspicuous nucleoli, and absent to scant, slightly tapering cytoplasm. As expected, the epithelial tumor cells typically exhibit a mostly round, vesicular nucleus and occasional prominent nucleoli. Unfortunately, in my experience, the vast majority of SS, including the biphasic variant, lack such cells on cytologic smears.2 This is usually not problematic, as the diagnosis is easily rendered when material is available for ancillary studies.

Both the monophasic and epithelial components usually express keratins and epithelial membrane antigen. Epithelial membrane antigen appears to represent a more sensitive marker than cytokeratin, especially for the poorly differentiated subtype of SS.3 Cytoplasmic CD99 reactivity has been reported in greater than 50% of tumors, causing a potential source of confusion with Ewing's sarcoma.4 Additionally, up to 20% of Ewing's sarcoma may show focal positivity for keratins.5

In a majority of cases, conventional cytogenetic analysis reveals a balanced relatively specific translocation t(X;18)(p11.2;11.2) with the fusion product SYT-SSX. This finding is observed in both biphasic and monophasic subtypes. Furthermore, we now know that two related but distinct X-chromosomal genes may be rearranged in this translocation, producing distinct fusion products, SYT-SSX1 and SYT-SSX2. Kawai et al.6 documented an association between SS subtype and the SYT-SSX subtype. In their series, biphasic tumors exclusively harbored the SYT-SSX1 rearrangement while monophasic fibrous types were predominantly (but not exclusively) found to have the SYT-SSX2 rearrangement. However, other investigators have not shown such a relationship.7 We should also point out that fine needle aspirates have proven successful in detecting the t(X;18) and its fusion product, SYT-SSX.8

Estimated 5-, 10-, and 15-year survival rates for SS range from 50 to 75%, 20 to 50%, and 10-45%, respectively. Risk factors for disease progression have included older age of patient (>25 years), large tumor size (>5 cm), poorly differentiated subtype (high nuclear grade), extensive tumor necrosis (>50%), presence of rhabdoid morphology, presence of bone and/or neurovascular invasion, and high tumor stage. SS containing the SYT-SSX1-type fusion appear to be associated with worse prognosis than those harboring the SYT-SSX2 subtype.6-7 At most institutions, SS is considered an intermediate to high grade sarcoma requiring not only surgical resection, but adjuvant therapy, including chemotherapy and/or radiation therapy. Adequate primary surgery appears to represent the most significant factor for local control and the prevention of recurrence.1

References

  1. Bergh P, Meis-Kindblom JM, Gherlinzoni F, et al. Synovial sarcoma: identification of low and high risk groups. Cancer 1999;85:2596-2607.
  2. Kilpatrick SE, Teot LA, Stanley MW, et al. Fine-needle aspiration biopsy of synovial sarcoma: a cytomorphologic analysis of primary, recurrent, and metastatic tumors. Am J Clin Pathol 1996;106:769-775.
  3. Folpe AL, Schmidt RA, Chapman D, et al. Poorly differentiated synovial sarcoma: immunohistochemical distinction from primitive neuroectodermal tumors and high-grade malignant peripheral nerve sheath tumors. Am J Surg Pathol 1998;22:673-682.
  4. Dei Tos AP, Wadden C, Calonje E, et al. Immunohistochemical demonstration of glycoprotein p30/32 MIC2 (CD99) in synovial sarcoma: a potential cause of diagnostic confusion. Appl Immunohistochem 1995;3:168-173.
  5. Gu M, Antonescu CR, Guiter G, et al. Cytokeratin immunoreactivity in Ewing's sarcoma: prevalence in 50 cases confirmed by molecular diagnostic studies. Am J Surg Pathol 2000;24:410-416.
  6. Kawai A, Woodruff J, Healey JH, et al. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 1998;338:153-160.
  7. Inagaki H, Nagasaka T, Otsuka T, et al. Association of SYT-SSX fusion types with proliferative activity and prognosis in synovial sarcoma. Mod Pathol 2000;13:482-488.
  8. Nilsson G, Wang M, Wejde J, et al. Reverse transcriptase polymerase chain reaction on fine needle aspirates for rapid detection of translocations in synovial sarcoma. Acta Cytol1998;42:1317-1324.