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Primary mediastinal synovial sarcoma: clinical, radiologic, and pathologic features in five cases

Paul H Hartel

Consultant Histopathologist, Sligo University Hospital, Sligo, Ireland

Section of Pulmonary and Critical Care Medicine, Dept. of Medicine, West Virginia University School of Medicine, Morgantown, WV, USA

E-mail : aa

John E. Parker

Section of Pulmonary and Critical Care Medicine, Dept. of Medicine, West Virginia University School of Medicine, Morgantown, WV, USA

DOI: 10.15761/NMBI.1000133

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Abstract

Primary mediastinal synovial sarcoma is rare and poses a diagnostic challenge particularly when unusual histologic features are present and t (x;18) is negative. Five cases of primary mediastinal synovial sarcoma were evaluated to define clinicopathologic features including unusual histology that may result in misdiagnosis. Clinically, compared with pulmonary synovial sarcomas, mediastinal synovial sarcomas occurred in younger patients and showed male predominance. Radiology images were reviewed. Histologically, tumors showed many identical characteristics of typical pulmonary and soft tissue synovial sarcomas with dense cellularity, interlacing fascicles, hyalinized stroma, and mast cell influx with focal hemangiopericytoma-like vasculature and calcification. In contrast, they showed no myxoid change, more infiltrative growth, and focal unusual histology not usually seen with soft tissue synovial sarcoma but typical of other neoplasms. These included Verocay bodies [1], papillary structures with fibrovascular cores [1], and adenomatoid change [1]. Immunohistochemistry demonstrated expected expression of focal cytokeratins, CD99, Bcl-2, and smooth muscle actin. Three of 5 tumors were positive for t (x;18), with one having no tissue remaining for testing. In conclusion, this small case series of mediastinal synovial sarcomas occurred in younger patients with male predominance compared with pulmonary synovial sarcoma, and had more infiltrative growth, less myxoid change and focal histology typical of other neoplasms. Awareness of focal unusual histology can prevent misdiagnosis particularly in t (x;18) negative tumors.

Key words

mediastinum, synovial sarcoma, histology, molecular translocation

Introduction

Primary mediastinal synovial sarcoma is an aggressive tumor sharing common clinical and histologic features with pulmonary and soft tissue synovial sarcoma. [1-5] Molecular testing for the pathognomonic t (x;18) chromosomal translocation has enabled diagnostic confirmation in the vast majority of cases. [6] In t (x;18) negative cases, diagnosis must rely on histologic and immunophenotypic features. The pathologic differential diagnosis of primary mediastinal synovial sarcoma is particularly challenging when histologic features unusual to synovial sarcoma, but common to other neoplasms are focally present. This challenge is compounded with negative t (x;18) findings. We evaluated 5 cases of primary mediastinal synovial sarcoma to compare clinicopathologic findings with those reported for pulmonary and soft tissue synovial sarcoma and bring awareness of unusual histology in this entity.

Materials and methods

Five cases of known mediastinal synovial sarcoma from 1981 to 2006 were retrieved from tissue archives. Clinical data were obtained from patient records. Hematoxylin and eosin stained sections were available for each case. Tumors were subtyped as monophasic or biphasic according to World Health Organization criteria. [7] Grading by tumor cell differentiation, mitotic rate, and necrosis was performed following the French Federation of Cancer Centers (FNCLCC) scheme. Unusual histologic features were noted, and immunohistochemistry was performed on paraffin embedded sections using commercially available antibodies (Table 1). Molecular analysis was performed on RNA extracted from paraffin embedded samples. SYT/SSX RNA fusion transcripts resulting from t (x;18) (p11; q11) translocation were detected using real-time reverse transcriptase-polymerase chain reaction. [8] Subtyping of SYT/SSX 1 and 2 fusion transcripts was performed using methods previously described. [8]

Table 1. Antibodies

Clone

Titer

Source

Pancytokeratin

AE1/AE3

1:200

Roche, Mannheim, Germany

Cytokeratin-7

OV TL12/30

1:160

Dako, Carpinteria, CA

Epithelial membrane antigen

E29

1:100

Dako, Carpinteria, CA

Cytokeratin 5/6

D5/16B4

1:20

Dako, Carpinteria, CA

Calretinin

CAL 3F5

1:50

Zymed, San Francisco, CA

Bcl-2

124

1:20

Dako, Carpinteria, CA

CD56

123C3

1:100

Caltag, Burlingame, CA

CD99

12E7

1:80

Dako, Carpinteria, CA

S-100

Polyclonal

1:800

Dako, Carpinteria, CA

Smooth Muscle Actin

1A4

1:800

Sigma, St. Louis, MO

Results

Clinical findings

Pertinent clinical features are presented in Table 2. The study group included 4 males and one female ranging from 10 to 71 years of age (mean, 36). The most common presenting symptoms were chest pain and shortness of breath. Surgical procedures of primary tumour included excision (n=2), and open biopsy (n=3). Local recurrence, metastases, and survival data were not different from pulmonary synovial sarcoma [9].

Table 2 Clinical findings

Mean age, years

36

Gender:

Male

Female

4

1

Common symptoms:

Chest pain

Dyspnea

2

1

Surgical Procedure

Excision of mass

Open biopsy

 

2

3

Radiology was not available in any of the mediastinal cases; however, radiologic images were available from 25 primary pulmonary synovial sarcomas which generally show virtually identical gross pathologic and histologic features [9]. To the extent that high resolution imaging is as sensitive as gross pathology including “1x” histology, results are at least comparable. On chest radiographs, tumors appeared homogeneous with sharply marginated borders. There was no cavitation, calcification, or lymphadenopathy. On computed tomography, these tumors showed homogeneous or heterogeneous enhancement without evidence of bone destruction or chest wall invasion. On magnetic resonance, T1-weighted and T2-weighted images showed a well-circumscribed mass without evidence of speculation or satellite nodules. T2-weighted images included nodular areas of intermediate signal intensity combined with discreet or cystic areas of high signal intensity most consistent with necrosis or hemorrhage (Figure 1).

Figure 1. Chest radiograph demonstrates a mass with smooth borders. Contrast-enhanced CT scan demonstrates a large low attenuation mass with rim enhancement (arrowhead) and internal septations. Axial T2-weighted (2110/57.6) magnetic resonance image shows greater contrast among internal components, with well-demarcated spaces (arrowheads) which suggest cysts.

Histologic findings

Histologic findings are presented in Table 3 and shown in Figures 2 and 3. Tumor size was not available, but tumors were described as soft, tan-gray masses with foci of necrosis. Histologically, tumors were monophasic (n=4) or biphasic (n=1). Tumors were grade 2 (n=5) with no grade 3 (poorly differentiated) tumors according to French Federation of Cancer Centers (FNCLCC) grading. Tumor cell morphology included spindle cells (n=3) or a combination of spindle and round/epithelioid cells (n=2). Mitoses ranged from 1 to 15 per 10 high power fields (mean, 7). Necrosis was present in 4 tumors (<50%).

Table 3 Histologic findings

Subtypes

Monophasic

Biphasic

Infiltrative growth

4

1

3

Typical histology

Dense interlacing fascicles

Eosinophilic stroma

Mast cell influx

HPC-like vasculature

Myxoid change

5

5

5

3

1

Unusual histology (common to other neoplasms, focally present)

Verocay body-like areas

Papillary structures

Adenomatoid areas

1

1

1

Figure 2. Typical histologic features of mediastinal synovial sarcoma, characteristically composed of (a) densely cellular interlacing fascicles, (b)eosinophilic stroma and (c) hemangiopericytoma-like vasculature.

Figure 3. Unusual histology that may lead to misdiagnosis include (a) Verocay body-like areas, (b) papillary formations, and (c) adenomatoid appearance.

Histologic features typical of pulmonary and soft tissue synovial sarcoma were seen and included dense cellularity (n=5), interlacing fascicles (n=5), and hyalinized or eosinophilic stroma (n=5). Mast cell influx (n=5), hemangiopericytoma-like vasculature (n=3), focal myxoid change (n=1) were also seen (Figure 2). Unusual histologic features were focal, noted in at least 1 but no more than 4 slides per case, varying from 4 to 90 high power fields and included Verocay body-like areas (n=1), well-formed papillary structures (n=1), and adenomatoid areas (n=1) (Figure 3).

Immunohistochemical and molecular findings

Immunohistochemical findings are presented in Table 4 and molecular findings in Table 5. Immunohistochemical studies showed focal positive membranous or cytoplasmic staining for epithelial markers including pancytokeratin (n=5), cytokeratin 7 (n=3), epithelial membrane antigen (n=1), and cytokeratin 5/6 (n=1). No tumors showed immunoreactivity for more than two cytokeratin markers. Diffuse immunoreactivity was seen with CD99 in three cases and Bcl-2 in two cases. Focal immunoreactivity was present with CD56 (n=2) and smooth muscle actin (n=2).

Table 4 Immunohistochemical findings

Pancytokeratin

5

Epithelial Membrane Antigen

1

Cytokeratin -7

3

Calretinin

0

Cytokeratin 5/6

2

CD99

3

Bcl-2

2

CD56

2

S-100

0

Smooth Muscle Actin

2

Table 5 Molecular findings

Total t(x;18) positive

Total SYT/SSX1

Total SYT/SSX2

Total t(x;18) positive, SSX unknown

Total t(x;18) negative

4

1

2

1

1

The chromosomal translocation t (x;18) was present in three cases studied in which two were fusion type SYT/SSX2 and one fusion type SYT/SSX1. One case was reported as t (x;18) positive without information on the SSX fusion type.

Discussion

Synovial sarcoma, although rare, is a primary mediastinal neoplasm sharing distinctive clinical and pathologic features with synovial sarcomas of lung and soft tissue. The presence of focal unusual histology characteristic of more common epithelial and mesenchymal tumors may lead to misdiagnosis. This is particularly problematic in small biopsies or in primary mediastinal synovial sarcomas that are negative for the pathognomonic t (x;18) translocation. We present five primary mediastinal synovial sarcoma cases for clinicopathologic characterization and comparison with pulmonary and soft tissue synovial sarcomas, including focal unusual histologic features.

Clinically, compared with pulmonary synovial sarcomas, this small series of mediastinal synovial sarcomas occurred in younger patients and showed male predominance. Histologically, tumors showed many identical characteristics of typical pulmonary and soft tissue synovial sarcomas with dense cellularity, interlacing fascicles, hyalinized stroma, and mast cell influx with focal hemangiopericytoma-like vasculature and calcification. In contrast, they showed less myxoid change, more infiltrative growth, and focal unusual histology not usually seen with soft tissue synovial sarcoma but typical of other neoplasms. The focal unusual histology in primary mediastinal synovial sarcoma can erroneously suggest more common primary and metastatic pulmonary neoplasms. Verocay body-like areas can occur  which are similar to those seen in malignant peripheral nerve sheath tumor.[10] The stromal background of malignant peripheral nerve sheath tumor, however, typically lacks hyalinization and appears more basophilic. Primary mediastinal synovial sarcoma is often immunoreactive for cytokeratin 7, a finding not generally seen in malignant peripheral nerve sheath tumor, [11, 12] and negative with S-100. Clinically, malignant peripheral nerve sheath tumors arise from nerve or neurofibroma and are associated with neurofibromatosis type I in approximately two-thirds of cases. [13]

Focal well-formed papillary or adenomatoid areas in primary mediastinal synovial sarcoma may be misinterpreted as carcinoma or malignant mesothelioma. In particular, pleomorphic carcinoma can present with spindle cell and adenocarcinoma components. Carcinomas are more cytologically atypical with greater pleomorphism than primary mediastinal synovial sarcoma. Carcinomas may have areas of squamous differentiation or contain tumor giant cells, features not observed in primary mediastinal synovial sarcoma. While cytokeratins are focally expressed in primary mediastinal synovial sarcoma, diffuse positivity for epithelial markers is not characteristic. However, it should be kept in mind that spindle cell carcinomas may also be only focally positive for cytokeratins. Carcinomas share an infiltrative growth pattern with this series of mediastinal synovial sarcomas, but in contrast show regional lymph node involvement, and/or widespread metastases. While mediastinal synovial sarcomas may express CK5/6, calretinin was negative in our cases.

We present five primary mediastinal synovial sarcoma cases occurring in younger patients with male predominance compared with pulmonary synovial sarcoma, and more infiltrative growth, less myxoid change and focal unusual histologic features that may erroneously suggest more common primary and metastatic pulmonary, mediastinal, or other primary-site neoplasms. This unusual histology may be particularly challenging in small biopsies or when t (x;18) is negative. Awareness of typical histology of mediastinal synovial sarcoma, their potential misleading unusual morphologic features, and prudent use of immunohistochemistry will prevent misdiagnosis, even in t (x;18)-negative cases.

Disclosure/conflict of interest

None of the authors have any disclosures or conflicts of interest.

References

  1. Zeren H, Moran CA, Suster S, Fishback NF, Koss MN (1995) Primary pulmonary sarcomas with features of monophasic synovial sarcoma: a clinicopathological, immunohistochemical, and ultrastructural study of 25 cases. Hum Pathol 26: 474-480. [Crossref]
  2. Bégueret H, Galateau-Salle F, Guillou L, Chetaille B, Brambilla E, et al. (2005) Primary intrathoracic synovial sarcoma: a clinicopathologic study of 40 t(x;18)-positive cases from the French Sarcoma Group and the Mesopath Group. Am J Surg Pathol 29: 339-346. [Crossref]
  3. Essary LR, Vargas SO, Fletcher CD (2002) Primary pleuropulmonary synovial sarcoma: reappraisal of a recently described anatomic subset. Cancer 94: 459-469. [Crossref]
  4. Okamoto S, Hisaoka M, Daa T, Hatakeyama K, Iwamasa T, et al. (2004) Primary pulmonary synovial sarcoma: a clinicopathologic, immunohistochemical, and molecular study of 11 cases. Hum Pathol 35: 850-856. [Crossref]
  5. Suster S, Moran CA (2005) Primary synovial sarcomas of the mediastinum: a clinicopathologic, immunohistochemical, and ultrastructural study of 15 cases. Am J Surg Pathol 29: 569-578. [Crossref]
  6. Fletcher CD, Unni KK, Mertens FE, World Health Organization Classification of Tumors (2002) Pathology and Genetics of Tumors of Soft Tissue and Bone. IARC Press: Lyon, France: 427. [Crossref]
  7. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC (2004) World Health Organization Classification of tumors of the Lung, Pleura, Thymus, and Heart. IARC Press: Lyon, France: 344. [Crossref]
  8. Bijwaard KE, Fetsch JF, Przygodzki R, Taubenberger JK, Lichy JH (2002) Detection of SYT-SSX fusion transcripts in archival synovial sarcomas by real-time reverse transcriptase-polymerase chain reaction. J Mol Diagn 4: 59-64. [Crossref]
  9. Hartel PH, Fanburg Smith JC, Frazier AA, Galvin JR, Lichy JH, et al. (2007) Primary pulmonary and mediastinal synovial sarcoma: a clinicopathologic study of 60 cases and comparison with five prior series. Mod Pathol 20: 760-769. [Crossref]
  10. Miettinen ME (2003) Diagnostic Soft Tissue Pathology. Churchill Livingstone, New York: 463-468.
  11. Smith TA, Machen SK, Fisher C, Goldblum JR (1999) Usefulness of cytokeratin subsets for distinguishing monophasic synovial sarcoma from malignant peripheral nerve sheath tumor. Am J Clin Pathol 112: 641-648. [Crossref]
  12. Machen SK, Fisher C, Gautam RS, Tubbs RR, Goldblum JR (1998) Utility of cytokeratin subsets for distinguishing poorly differentiated synovial sarcoma from peripheral primitive neuroectodermal tumour. Histopathology 33: 501-507. [Crossref]
  13. Kleihues P, Cavenee WKE, World Health Organization Classification of Tumors (2000) Pathology and Genetics of Tumors of the Central Nervous System: 172-174.

Editorial Information

Editor-in-Chief

Article Type

Research Article

Publication history

Received: March 07, 2018
Accepted: March 17, 2018
Published: March 30, 2018

Copyright

©2018 Hartel PH. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Hartel PH, Parker JE (2018) Primary mediastinal synovial sarcoma: clinical, radiologic, and pathologic features in five cases. Nucl Med Biomed Imaging 3: DOI: 10.15761/NMBI.1000133

Corresponding author

Dr Paul Hartel

Sligo University Hospital, Histology, Level 4, The Mall Sligo, Co. Sligo, Ireland

Table 1. Antibodies

Clone

Titer

Source

Pancytokeratin

AE1/AE3

1:200

Roche, Mannheim, Germany

Cytokeratin-7

OV TL12/30

1:160

Dako, Carpinteria, CA

Epithelial membrane antigen

E29

1:100

Dako, Carpinteria, CA

Cytokeratin 5/6

D5/16B4

1:20

Dako, Carpinteria, CA

Calretinin

CAL 3F5

1:50

Zymed, San Francisco, CA

Bcl-2

124

1:20

Dako, Carpinteria, CA

CD56

123C3

1:100

Caltag, Burlingame, CA

CD99

12E7

1:80

Dako, Carpinteria, CA

S-100

Polyclonal

1:800

Dako, Carpinteria, CA

Smooth Muscle Actin

1A4

1:800

Sigma, St. Louis, MO

Table 2 Clinical findings

Mean age, years

36

Gender:

Male

Female

4

1

Common symptoms:

Chest pain

Dyspnea

2

1

Surgical Procedure

Excision of mass

Open biopsy

 

2

3

Table 3 Histologic findings

Subtypes

Monophasic

Biphasic

Infiltrative growth

4

1

3

Typical histology

Dense interlacing fascicles

Eosinophilic stroma

Mast cell influx

HPC-like vasculature

Myxoid change

5

5

5

3

1

Unusual histology (common to other neoplasms, focally present)

Verocay body-like areas

Papillary structures

Adenomatoid areas

1

1

1

Table 4 Immunohistochemical findings

Pancytokeratin

5

Epithelial Membrane Antigen

1

Cytokeratin -7

3

Calretinin

0

Cytokeratin 5/6

2

CD99

3

Bcl-2

2

CD56

2

S-100

0

Smooth Muscle Actin

2

Table 5 Molecular findings

Total t(x;18) positive

Total SYT/SSX1

Total SYT/SSX2

Total t(x;18) positive, SSX unknown

Total t(x;18) negative

4

1

2

1

1

Figure 1. Chest radiograph demonstrates a mass with smooth borders. Contrast-enhanced CT scan demonstrates a large low attenuation mass with rim enhancement (arrowhead) and internal septations. Axial T2-weighted (2110/57.6) magnetic resonance image shows greater contrast among internal components, with well-demarcated spaces (arrowheads) which suggest cysts.

Figure 2. Typical histologic features of mediastinal synovial sarcoma, characteristically composed of (a) densely cellular interlacing fascicles, (b)eosinophilic stroma and (c) hemangiopericytoma-like vasculature.

Figure 3. Unusual histology that may lead to misdiagnosis include (a) Verocay body-like areas, (b) papillary formations, and (c) adenomatoid appearance.