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Monophasic epithelial synovial sarcoma initially diagnosed as metastatic adenocarcinoma of unknown primary
Human Pathology: Case Reports 17 (2019) 200307
Contents lists available at ScienceDirect
Human Pathology: Case Reports journal homepage: www.elsevier.com/locate/ehpc
Case Report
Monophasic epithelial synovial sarcoma initially diagnosed as metastatic adenocarcinoma of unknown primary
T
Donghwa Baeka, Andreia Barbieria, Alberto G. Ayalaa, Kwang M. Leeb, Myoung J. Jub, Jae Y. Roa,
⁎
a b
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX, United States of America Department of Pathology, Jeonju Jesus Hospital, Jeonju, Republic of Korea
ARTICLE INFO
ABSTRACT
Keywords: Monophasic synovial sarcoma Epithelial type Adenocarcinoma TLE1 immunostain
Monophasic epithelial synovial sarcoma is extremely rare, and its existence has been debated. We report a case of monophasic epithelial synovial sarcoma, which was initially diagnosed as metastatic adenocarcinoma. A 45year-old woman presented with a tender pelvic mass, whose morphology was consistent with a glandular neoplasm. The mass was misdiagnosed as metastatic adenocarcinoma of unknown primary, and was treated as such. The tumor recurred 12 years later; it showed biphasic morphology including glandular and spindle sarcomatoid components. TLE1 immunoreactivity of the second tumor supported diagnosis of biphasic synovial sarcoma. The original lesion was reexamined and revealed very focal minor spindle tumor foci admixed with an extensive glandular background. The TLE1 immunostain was strongly positive in the initial lesion, thus confirming diagnosis of epithelial-predominant synovial sarcoma. This case emphasizes the importance of generous sampling and the use of TLE1 staining when soft tissue tumors show predominantly epithelial architectures without an apparent primary site.
1. Introduction Synovial sarcoma (SS) is a clinically and morphologically distinct entity with two subtypes—biphasic and monophasic [1]. The monophasic subtype is further divided into spindle and epithelial SS. The biphasic and monophasic spindle types are more common and compose most SS cases. However, monophasic epithelial SS is very rare and nearly impossible to identify without molecular or cytogenetic analysis [2]. Monophasic epithelial SS can be misdiagnosed because this type of tumor is morphologically indistinguishable from metastatic adenocarcinoma. Herein, we report a case of monophasic epithelial SS that was originally misdiagnosed as metastatic adenocarcinoma of unknown primary. 2. Case report A 45-year-old woman presented with a tender abdominal mass and vaginal bleeding, in 2006. The patient underwent pelvic computed tomography (CT) scan, which revealed a mass (5.6 × 4.4 cm) on the left side of the pelvis (Fig. 1) and an ovarian cyst (3.0 × 2.2 cm) on the right side. The ovarian cyst on the right side had a benign appearance, and was left intact. The resected pelvic tumor was a well-circumscribed,
firm mass with a homogenous pale gray-to-tan cut surface. No hemorrhage, necrosis or cystic change was seen. On microscopic examination, the tumor primarily consisted of a gland-forming neoplasm with a minor component of spindle fibrous stroma (Fig. 2A). The glands formed branching tubular architectures with focal gland fusion, cribriform, and papillary structures. The glandular lumina contained variable amounts of mixed eosinophilic and bluish mucinous secretions (Fig. 2B). The epithelial cells lining the glandular structures were cuboidal to low columnar, and contained oval round nuclei with finely dispersed chromatin and inconspicuous nucleoli. No significant cytologic atypia, necrosis or mitotic activity was seen. The supporting stroma between the tumor glands was composed of spindle cells and focal thick collagen (Fig. 2C). Areas of cellular spindle cell component were rarely seen, and represented < 10% of the tumor. There were scattered microcalcifications in the lumen and fibrous stroma. (Fig. 2D) The tumor was present at the margins. An initial diagnosis of metastatic adenocarcinoma was made. Extensive investigations, including upper and lower GI endoscopy, pelvic magnetic resonance imaging (MRI), bone scan, and tumor marker panels, failed to reveal the primary site. The patient received postoperative radiation therapy in total dose of 53 Gray over 33 fractions and 6 cycles of 5fluorouracil. Neither recurrence nor metastasis developed in the next
⁎ Corresponding author at: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, 6565 Fannin Street, Houston, TX, United States of America. E-mail address: [email protected] (J.Y. Ro).
https://doi.org/10.1016/j.hpcr.2019.200307 Received 7 January 2019; Received in revised form 6 March 2019; Accepted 11 March 2019 2214-3300/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Human Pathology: Case Reports 17 (2019) 200307
D. Baek, et al.
name is a misnomer as the tumor does not exhibit synovial differentiation nor has a higher frequency of occurrence inside the joints. SS may arise at any anatomical site, but is more commonly seen in deep peri-articular soft tissue. SS is primarily encountered in adolescents or young adults at 15–40 years of age. Males are affected more often than females with a male to female ratio of 1.2:1. SS exhibits a wide morphologic spectrum and has two major subtypes—monomorphic fibrous and biphasic. The monophasic fibrous type is the most common, and accounts for 72% of adult tumors and 55% of child tumors [3,4]. This tumor subtype is composed of spindle cells with either fascicular, palisading, or herringbone patterns. The cells have scant cytoplasm and hyperchromatic nuclei, and may produce stromal mucin. Biphasic tumors have the same spindle cell component with variable proportions of epithelial component. The epithelial component can be either glandular or solid. The glandular lumen is lined with cuboidal or columnar cells, and may have epithelial mucin. The cells have oval and vesicular nuclei and conspicuous eosinophilic cytoplasm, which make them stand out in the background of spindle cells. Our case is a notable exception because the epithelial (most commonly glandular) component was predominant, thereby representing a monophasic “epithelial” SS, an entity that is considered extremely rare. To the best of our knowledge, only 11 cases of monophasic epithelial SS including our case have been reported heretofore (Table 1) [5–12]. The age of the patients ranged from 19 to 78 years, with an average age of 45.2 years. Four cases involved males, and the rest occurred in females. Seven cases arose in the extremities, two cases in the abdominopelvic area, and the other two cases in the head and neck area. The tumor sizes ranged from 3 to 12 cm. Only one of the cases was confirmed by molecular methods, which demonstrated presence of the translocation t (X;18) [11]. The rarity of this type of SS may stem from the morphologic overlap with adenocarcinoma, which may be the reason why these tumors are misdiagnosed. However, we believe that more cases of monophasic epithelial SS will be reported in the future, because nowadays this entity can be diagnosed by TLE1 immunostaining and other molecular studies with a higher level of certainty. Despite its rarity, recognition of this entity is imperative in order to avoid misdiagnosis of the tumor as metastatic adenocarcinoma, especially when the main component of the tumor is glandular and no other apparent primary adenocarcinoma sites are found. Generous sampling to demonstrate a minor spindle cell component, immunohistochemical staining, including TLE1, and confirmation by detection of the translocation t(X;18) are recommended to diagnose monophasic epithelial SS. Differential diagnoses other than metastatic adenocarcinoma include carcinosarcoma, malignant nerve sheath tumor (MPNST), epithelioid schwannoma, angiosarcoma, epithelioid sarcoma, and adnexal carcinoma [6,9,11,13]. Not to mention the effort to find the primary site, extensive sampling of the tumor should be pursued in these cases to demonstrate the presence of cellular spindle cell component and thick ropey collagen. Notwithstanding their scant amounts, the aforementioned components were present in nearly all the previously reported cases. Thus, cellular areas of spindle cells and thick ropey collagen can be strong indicators to raise suspicion for SS in differential diagnosis. Immunohistochemical and molecular studies can provide insight in challenging cases such as the one presented herein. Conventional immunohistochemical markers for SS include cytokeratin, EMA, CD99, and Bcl-2. SOX-10 rather than S100 may be needed to exclude MPNST or epithelioid schwannoma in epithelial SS [14]. TLE1, a relatively newer marker, is also very helpful for diagnosis of SS. Strong and diffuse nuclear staining for TLE1 is highly suggestive of SS [15]. Although one study showed TLE1 is not entirely specific for SS [16], it is generally accepted that TLE1 is a reliable marker for SS especially in the setting of unclassifiable high-grade sarcoma [17]. Nevertheless, the result of this test should be evaluated in conjunction with proper
Fig. 1. Nonenhanced pelvic computed tomography revealed a mass (5.6 cm) on left side of the pelvis (arrow), initially diagnosed in 2006.
12 years of follow-up. Twelve years after the initial presentation, the patient returned with a tender inguinal mass. An abdominal pelvic CT scan revealed a pelvic mass on the left side (4.6 cm), at the same site where the first tumor was resected in 2006 (Fig. 3). Once again, extensive studies failed to demonstrate the primary site. Clinically, the second pelvic mass was considered recurrent and excised. The recurrent tumor showed biphasic histology with glandular and spindle sarcomatoid components (Fig. 4A). The cellular spindle components consisted of well-oriented plump spindle cells. These cells consist of alternating darkly stained cells and lightly stained cells arranged in fascicles. The cells were relatively uniform with a small amount of indistinct cytoplasm and oval to short spindle, darkly stained nuclei without prominent nucleoli. Mitoses were occasionally seen, and < 10/10 high power fields were counted. The epithelial tumor component formed solid cords, nests, and glandular structures. The epithelial cells were cuboidal to low columnar with round to oval vesicular nuclei, abundant cytoplasm, and distinct cell boundaries. The glandular lumina contained granular or homogeneous eosinophilic secretions. These two tumor components showed close apposition in a way that the spindle tumor cells surrounded the epithelial tumor component. Scattered thick ropey collagen was seen within the spindle tumor component but no calcifications were observed. Immunohistochemical staining for TLE1 (1:100 dilution, 15-min incubation; clone 1F5, Cell Marque, Rocklin, CA) was performed on the initial (Fig. 2E and F) and recurrent (Fig. 4B) tumors. Both tumors exhibited strong nuclear positivity within epithelial and spindle tumor cells. Pancytokeratin (AE1/AE3), EMA and CK7 were strongly positive in gland-forming tumor cells in both tumors but CK20 was negative. Spindle cells were negative for AE1/AE3, EMA, CK7, and CK20 in both tumors. Bcl-2 and CD99 were positive in spindle cell components of both tumors, but inconsistent in glandular components. S100 and SOX10 are negative for spindle and glandular components in both tumors. 3. Discussion SS is a mesenchymal tumor of unknown origin, which is characterized by the chromosomal translocation t(X;18)(p11;q11) [1]. The 2
Human Pathology: Case Reports 17 (2019) 200307
D. Baek, et al.
(a)
(b)
(c)
(d)
(e)
(f)
Fig. 2. (A) Original resected tumor mainly shows complex glandular structures with anastomosing and papillary configuration. Focal cellular spindle area (circled) is noted. (H&E, ×50) (B) The gland lumen contains mixed eosinophilic and bluish mucinous secretion. The glandular lining cells have oval to round nuclei with vesicular chromatin and a moderate amount of eosinophilic cytoplasm. Nucleoli are not present or are inconspicuous. (H&E, ×200) (C) The focal cellular area is composed of spindle cells and dense collagenous fibers. Note that the fibrous area is more cellular than is expected in desmoplastic reaction. No significant cytologic atypia or mitotic activity is seen in both glandular and spindle cell components. (H&E, ×200) (D) Intraluminal calcifications. (H&E, ×100) (E, F) TLE1 immunostain in the initial tumor. Nuclear immunopositivity is present not only in glandular but also in spindle stromal element (arrows). (TLE1, ×200).
3
Human Pathology: Case Reports 17 (2019) 200307
D. Baek, et al.
diagnosis had been initially made in 2006. Notably, our case had a very unusual clinical course: no recurrence or metastasis occurred until 12 years after resection of the initial tumor, which was misdiagnosed as metastatic adenocarcinoma of unknown primary. Additionally, it is likely that monophasic epithelial SS confers a better prognosis than other subtypes of SS. Notwithstanding the dearth of previous studies on monophasic epithelial SS, Cagle et al. reported that SS with > 50% glandular differentiation, i.e., “highly glandular” SS, has lower 36month recurrence rates and higher survival rates as compared to SS with < 50% of glandular differentiation or monophasic fibrous SS [20]. Other rare but clinically important variants include calcifying SS and poorly differentiated SS. Calcifying SS is characterized by scattered and irregular foci of calcifications, which are present in 30% of SS [21]. Calcifications are an important radiologic clue of SS [22]. Furthermore, calcifying SS has a significantly better prognosis than tumors without calcifications [23]. Poorly differentiated SS can be considered a form of progressed tumor rather than a separate subtype. This variant represents rounded or spindled cells with severe nuclear atypia and high mitotic activity [1]. These tumors tend to behave aggressively and have poorer prognosis [24,25]. The salient features of each SS subtype are summarized in Table 2. 4. Conclusion Monophasic epithelial SS is extremely rare, and has been a controversial entity. Morphologic distinction from metastatic adenocarcinoma can be challenging, and extensive sampling to reveal a cellular spindle cell tumor component is critical. Immunohistochemical staining with TLE1 or molecular studies to detect the t(X;18) translocation is a helpful tool for diagnosis of monophasic epithelial SS. Recognition and proper diagnosis of monophasic epithelial SS is of utmost importance given the different treatment modalities and better prognostic implications as compared to metastatic adenocarcinoma or other types of SS.
Fig. 3. Nonenhanced pelvic computed tomography showed the recurrent mass (4.6 cm) on left side of pelvis (arrow), detected in 2018.
histological and conventional immunohistochemical markers in the appropriate context [2]. For instance, NY-ESO-1 is also an emerging diagnostic and potentially therapeutic marker for SS [18] but this stain is not widely available in daily routine practice yet. Currently, the most reliable diagnostic test for SS is the chromosomal translocation t(X;18) (p11.2;q11.2), which is present in over 90% of SS cases [2,19]. Furthermore, it is important to appreciate and diagnose this rare SS variant in light of the therapeutic and prognostic implications. Complete surgical excision with free margins would have been performed and chemoradiation with a different regimen (ifosfamide rather than 5-FU) would have been administered to our patient if the correct
Funding disclosure We have no financial interest or conflict of interest in association with this work.
(a)
(b)
Fig. 4. (A) Recurrent tumor with biphasic morphology. Tumor shows both glandular and spindle sarcomatoid components, which are apposed to each other. Scattered thick ropey collagen is noted. (H&E, ×200) (B) TLE1 immunostaining of the recurrent tumor demonstrates strong and diffuse nuclear positivity, seen in both epithelial and spindle tumor components. (TLE1, ×200).
4
5
20
47 19
67 48
58 45
Richard M et al. [7]
Weidner et al. [8] K Tajima et al. (1999) [9]
H. Bukawa et al. [10] I Weinreb et al. [11]
Xiohua Jiang et al. [12] Our case
M F
M F
M F
F
M
Right TMJ Left lower leg, posterior tibial nerve Left sphenoidal sinus Left pelvic area
Right distal thigh Left forearm
Left medial thigh
Right flank
Left knee
Right leg Left arm, axilla
Location
NA 5.6
5 8.7
5 3
5
12
7.5c
12 NAc
Sizea Cuboidal or columnar cells with glands, trabeculae, papillary formations Primary: classic biphasic Recurrent: compact aggregates of epithelial cells in a dense, fibrous matrix, cells in files Primary: biphasic with histiocytes; papillary or glandular patterns in the epithelial component Recurrent: uniformly glandular; some undifferentiated areas Primary: 90% glandular nests, frequent intraluminal papillae, squamous differentiation; 10% stromal Recurrent: 90% stromal; 10% atrophic glands 90% cribriforming glands; some papillary, minute spindle components with similar cellularity as desmoplasia Highly vascular, epithelioid tumor cells in a peritheliomatous pattern; a focus of spindle cell area (< 5%) Cuboidal, columnar, polygonal; occasional squamous pearls and keratinization; no spindle cell components Glands with only minute spindle cell components Primary: mucinous secretions, glands, micropapillae, cytologic atypia; < 1% stromal component Recurrent: the same as the primary Atypical proliferating epithelial cells arranged like irregular glands Primary: mostly complex glandular architectures; minor cellular stromal element; foci of intraluminal calcifications; no cytologic atypia or mitotic activity Recurrent: classic biphasic
Histopathology
Abbreviations: TMJ, temporomandibular joint. a Largest dimension in centimeters b Theses two cases were recurrent tumors. The numbers here represent the age when the primary tumor was diagnosed. c Size of the recurrent tumor
25
F
37b
JM Mirra et al. [6]
F F
78 53b
KB Farris et al. [5]
Sex
Age
Reference
Table 1 Previously reported cases of monophasic epithelial synovial sarcoma.
No metastasis for 2 years follow up Recurred at the 3rd month; recurrence free for 11 months thereafter Disease-free for 50 months of follow up Recurred after 12 years
Disease-free for 8 months of follow up Disease free for 4 years of follow up
Disease-free for 30 months of follow up
Recurred as a biphasic tumor after 2 years
Recurred after 13 years
No metastasis for 6 years of follow-up Recurred after 6.5 years
Course
D. Baek, et al.
Human Pathology: Case Reports 17 (2019) 200307
Human Pathology: Case Reports 17 (2019) 200307
[1] C.D.M. Fletcher, World Health Organization, International Agency for Research on Cancer, WHO Classification of Tumours of Soft Tissue and Bone, IARC Press, Lyon, 2013. [2] K. Thway, C. Fisher, Synovial sarcoma: defining features and diagnostic evolution, Ann. Diagn. Pathol. 18 (2014) 369–380. [3] L. Guillou, J. Benhattar, F. Bonichon, 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 (2004) 4040–4050. [4] A. Kerouanton, I. Jimenez, C. Cellier, et al., Synovial sarcoma in children and adolescents, J. Pediatr. Hematol. Oncol. 36 (2014) 257–262. [5] K.B. Farris, R.J. Reed, Monophasic, glandular, synovial sarcomas and carcinomas of the soft tissues, Archiv. Pathol. Lab. Med. 106 (1982) 129–132. [6] J.M. Mirra, S. Wang, S. Bhuta, Synovial sarcoma with squamous differentiation of its mesenchymal glandular elements. A case report with light-microscopic, ultramicroscopic, and immunologic correlation, Am. J. Surg. Pathol. 8 (1984) 791–796. [7] R.M. Majeste, E.N. Beckman, Synovial sarcoma with an overwhelming epithelial component, Cancer 61 (1988) 2527–2531. [8] N. Weidner, R. Goldman, J. Johnston, Epithelioid monophasic synovial sarcoma, Ultrastruct. Pathol. 17 (1993) 287–294. [9] K. Tajima, S. Fuyama, H. Yamaguchi, et al., Pure monophasic, epithelial synovial sarcoma without a spindle cell component, Histopathology 34 (1999) 78–81. [10] H. Bukawa, A. Kawabata, A. Murano, et al., Monophasic epithelial synovial sarcoma arising in the temporomandibular joint, Int. J. Oral Maxillofac. Surg. 36 (2007) 762–765. [11] I. Weinreb, B. Perez-Ordonez, A. Guha, et al., Mucinous, gland predominant synovial sarcoma of a large peripheral nerve: a rare case closely mimicking metastatic mucinous carcinoma, J. Clin. Pathol. 61 (2008) 672–676. [12] X. Jiang, Q. Huang, J. Tang, et al., Monophasic epithelial synovial sarcoma accompanied by an inverted papilloma in the sphenoid sinus, Case Rep. Med. 2012 (2012) 379720. [13] Y. Miki, K. Thway, Malignant peripheral nerve sheath tumor with divergent glandular differentiation, Int. J. Surg. Pathol. 25 (2017) 310–313. [14] J.R. Karamchandani, T.O. Nielsen, M. van de Rijn, et al., Sox10 and S100 in the diagnosis of soft-tissue neoplasms, Appl. Immunohistochem. Mol. Morphol. 20 (2012) 445–450. [15] J. Terry, T. Saito, S. Subramanian, et al., TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies, Am. J. Surg. Pathol. 31 (2007) 240–246. [16] K. Kosemehmetoglu, J.A. Vrana, A.L. Folpe, TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms, Mod. Pathol. 22 (2009) 872–878. [17] A.L. Valente, J. Tull, S. Zhang, Specificity of TLE1 expression in unclassified highgrade sarcomas for the diagnosis of synovial sarcoma, Appl. Immunohistochem. Mol. Morphol. 21 (2013) 408–413. [18] J.P. Lai, P.F. Robbins, M. Raffeld, et al., NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis, Mod. Pathol. 25 (2012) 854–858. [19] A.A. Sandberg, J.A. Bridge, Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Synovial sarcoma, Cancer Genet. Cytogenet. 133 (2002) 1–23. [20] L.A. Cagle, J.M. Mirra, F.K. Storm, et al., Histologic features relating to prognosis in synovial sarcoma, Cancer 59 (1987) 1810–1814. [21] N.L. Cadman, E.H. Soule, P.J. Kelly, Synovial sarcoma; an analysis of 34 tumors, Cancer 18 (1965) 613–627. [22] M.D. Murphey, M.S. Gibson, B.T. Jennings, et al., From the archives of the AFIP: imaging of synovial sarcoma with radiologic-pathologic correlation, Radiographics: A Review Publication of the Radiological Society of North America, vol. 26, Inc, 2006, pp. 1543–1565. [23] J. Varela-Duran, F.M. Enzinger, Calcifying synovial sarcoma, Cancer 50 (1982) 345–352. [24] M. van de Rijn, F.G. Barr, Q.B. Xiong, et al., Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features, Am. J. Surg. Pathol. 23 (1999) 106–112. [25] M.V. de Silva, A.D. McMahon, L. Paterson, et al., Identification of poorly differentiated synovial sarcoma: a comparison of clinicopathological and cytogenetic features with those of typical synovial sarcoma, Histopathology 43 (2003) 220–230.
Poor
Either monophasic or biphasic; round or spindle cells with nuclear atypia, mitoses, or necrosis Round cell neoplasms (e.g., EFT, neuroblastoma, rhabdomyosarcoma, lymphoma, etc.)
References
Abbreviations: MPNST, malignant peripheral nerve sheath tumor; SS, synovial sarcoma.
Intermediate Prognosis
Spindle cell neoplasms (e.g., fibrosarcoma, leiomyosarcoma, MPNST, etc.) Intermediate
Histology
Differential diagnosis
Biphasic neoplasms (e.g., MPNST, mesothelioma, carcinosarcoma, etc.)
Good
Either monophasic or biphasic; irregular calcifications Extraskeletal osteosarcoma, myositis ossificans, ossifying fibroma, etc. Good Epithelial (most commonly glandular) cell dominant Metastatic adenocarcinoma, adnexal carcinoma, carcinosarcoma, etc.
20% 30%
The authors thank Dr. Helen Chifotides for her editorial support.
72% in adults 55% in children Spindle cell dominant
28% in adults 45% in children Biphasic
Very rare
Acknowledgment
Incidence
Monophasic fibrous SS
Table 2 Salient features of different types of synovial sarcoma.
Biphasic SS
Monophasic epithelial SS
Calcifying SS
Poorly differentiated SS
D. Baek, et al.
6
Contents lists available at ScienceDirect
Human Pathology: Case Reports journal homepage: www.elsevier.com/locate/ehpc
Case Report
Monophasic epithelial synovial sarcoma initially diagnosed as metastatic adenocarcinoma of unknown primary
T
Donghwa Baeka, Andreia Barbieria, Alberto G. Ayalaa, Kwang M. Leeb, Myoung J. Jub, Jae Y. Roa,
⁎
a b
Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, Houston, TX, United States of America Department of Pathology, Jeonju Jesus Hospital, Jeonju, Republic of Korea
ARTICLE INFO
ABSTRACT
Keywords: Monophasic synovial sarcoma Epithelial type Adenocarcinoma TLE1 immunostain
Monophasic epithelial synovial sarcoma is extremely rare, and its existence has been debated. We report a case of monophasic epithelial synovial sarcoma, which was initially diagnosed as metastatic adenocarcinoma. A 45year-old woman presented with a tender pelvic mass, whose morphology was consistent with a glandular neoplasm. The mass was misdiagnosed as metastatic adenocarcinoma of unknown primary, and was treated as such. The tumor recurred 12 years later; it showed biphasic morphology including glandular and spindle sarcomatoid components. TLE1 immunoreactivity of the second tumor supported diagnosis of biphasic synovial sarcoma. The original lesion was reexamined and revealed very focal minor spindle tumor foci admixed with an extensive glandular background. The TLE1 immunostain was strongly positive in the initial lesion, thus confirming diagnosis of epithelial-predominant synovial sarcoma. This case emphasizes the importance of generous sampling and the use of TLE1 staining when soft tissue tumors show predominantly epithelial architectures without an apparent primary site.
1. Introduction Synovial sarcoma (SS) is a clinically and morphologically distinct entity with two subtypes—biphasic and monophasic [1]. The monophasic subtype is further divided into spindle and epithelial SS. The biphasic and monophasic spindle types are more common and compose most SS cases. However, monophasic epithelial SS is very rare and nearly impossible to identify without molecular or cytogenetic analysis [2]. Monophasic epithelial SS can be misdiagnosed because this type of tumor is morphologically indistinguishable from metastatic adenocarcinoma. Herein, we report a case of monophasic epithelial SS that was originally misdiagnosed as metastatic adenocarcinoma of unknown primary. 2. Case report A 45-year-old woman presented with a tender abdominal mass and vaginal bleeding, in 2006. The patient underwent pelvic computed tomography (CT) scan, which revealed a mass (5.6 × 4.4 cm) on the left side of the pelvis (Fig. 1) and an ovarian cyst (3.0 × 2.2 cm) on the right side. The ovarian cyst on the right side had a benign appearance, and was left intact. The resected pelvic tumor was a well-circumscribed,
firm mass with a homogenous pale gray-to-tan cut surface. No hemorrhage, necrosis or cystic change was seen. On microscopic examination, the tumor primarily consisted of a gland-forming neoplasm with a minor component of spindle fibrous stroma (Fig. 2A). The glands formed branching tubular architectures with focal gland fusion, cribriform, and papillary structures. The glandular lumina contained variable amounts of mixed eosinophilic and bluish mucinous secretions (Fig. 2B). The epithelial cells lining the glandular structures were cuboidal to low columnar, and contained oval round nuclei with finely dispersed chromatin and inconspicuous nucleoli. No significant cytologic atypia, necrosis or mitotic activity was seen. The supporting stroma between the tumor glands was composed of spindle cells and focal thick collagen (Fig. 2C). Areas of cellular spindle cell component were rarely seen, and represented < 10% of the tumor. There were scattered microcalcifications in the lumen and fibrous stroma. (Fig. 2D) The tumor was present at the margins. An initial diagnosis of metastatic adenocarcinoma was made. Extensive investigations, including upper and lower GI endoscopy, pelvic magnetic resonance imaging (MRI), bone scan, and tumor marker panels, failed to reveal the primary site. The patient received postoperative radiation therapy in total dose of 53 Gray over 33 fractions and 6 cycles of 5fluorouracil. Neither recurrence nor metastasis developed in the next
⁎ Corresponding author at: Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Weill Medical College of Cornell University, 6565 Fannin Street, Houston, TX, United States of America. E-mail address: [email protected] (J.Y. Ro).
https://doi.org/10.1016/j.hpcr.2019.200307 Received 7 January 2019; Received in revised form 6 March 2019; Accepted 11 March 2019 2214-3300/ © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Human Pathology: Case Reports 17 (2019) 200307
D. Baek, et al.
name is a misnomer as the tumor does not exhibit synovial differentiation nor has a higher frequency of occurrence inside the joints. SS may arise at any anatomical site, but is more commonly seen in deep peri-articular soft tissue. SS is primarily encountered in adolescents or young adults at 15–40 years of age. Males are affected more often than females with a male to female ratio of 1.2:1. SS exhibits a wide morphologic spectrum and has two major subtypes—monomorphic fibrous and biphasic. The monophasic fibrous type is the most common, and accounts for 72% of adult tumors and 55% of child tumors [3,4]. This tumor subtype is composed of spindle cells with either fascicular, palisading, or herringbone patterns. The cells have scant cytoplasm and hyperchromatic nuclei, and may produce stromal mucin. Biphasic tumors have the same spindle cell component with variable proportions of epithelial component. The epithelial component can be either glandular or solid. The glandular lumen is lined with cuboidal or columnar cells, and may have epithelial mucin. The cells have oval and vesicular nuclei and conspicuous eosinophilic cytoplasm, which make them stand out in the background of spindle cells. Our case is a notable exception because the epithelial (most commonly glandular) component was predominant, thereby representing a monophasic “epithelial” SS, an entity that is considered extremely rare. To the best of our knowledge, only 11 cases of monophasic epithelial SS including our case have been reported heretofore (Table 1) [5–12]. The age of the patients ranged from 19 to 78 years, with an average age of 45.2 years. Four cases involved males, and the rest occurred in females. Seven cases arose in the extremities, two cases in the abdominopelvic area, and the other two cases in the head and neck area. The tumor sizes ranged from 3 to 12 cm. Only one of the cases was confirmed by molecular methods, which demonstrated presence of the translocation t (X;18) [11]. The rarity of this type of SS may stem from the morphologic overlap with adenocarcinoma, which may be the reason why these tumors are misdiagnosed. However, we believe that more cases of monophasic epithelial SS will be reported in the future, because nowadays this entity can be diagnosed by TLE1 immunostaining and other molecular studies with a higher level of certainty. Despite its rarity, recognition of this entity is imperative in order to avoid misdiagnosis of the tumor as metastatic adenocarcinoma, especially when the main component of the tumor is glandular and no other apparent primary adenocarcinoma sites are found. Generous sampling to demonstrate a minor spindle cell component, immunohistochemical staining, including TLE1, and confirmation by detection of the translocation t(X;18) are recommended to diagnose monophasic epithelial SS. Differential diagnoses other than metastatic adenocarcinoma include carcinosarcoma, malignant nerve sheath tumor (MPNST), epithelioid schwannoma, angiosarcoma, epithelioid sarcoma, and adnexal carcinoma [6,9,11,13]. Not to mention the effort to find the primary site, extensive sampling of the tumor should be pursued in these cases to demonstrate the presence of cellular spindle cell component and thick ropey collagen. Notwithstanding their scant amounts, the aforementioned components were present in nearly all the previously reported cases. Thus, cellular areas of spindle cells and thick ropey collagen can be strong indicators to raise suspicion for SS in differential diagnosis. Immunohistochemical and molecular studies can provide insight in challenging cases such as the one presented herein. Conventional immunohistochemical markers for SS include cytokeratin, EMA, CD99, and Bcl-2. SOX-10 rather than S100 may be needed to exclude MPNST or epithelioid schwannoma in epithelial SS [14]. TLE1, a relatively newer marker, is also very helpful for diagnosis of SS. Strong and diffuse nuclear staining for TLE1 is highly suggestive of SS [15]. Although one study showed TLE1 is not entirely specific for SS [16], it is generally accepted that TLE1 is a reliable marker for SS especially in the setting of unclassifiable high-grade sarcoma [17]. Nevertheless, the result of this test should be evaluated in conjunction with proper
Fig. 1. Nonenhanced pelvic computed tomography revealed a mass (5.6 cm) on left side of the pelvis (arrow), initially diagnosed in 2006.
12 years of follow-up. Twelve years after the initial presentation, the patient returned with a tender inguinal mass. An abdominal pelvic CT scan revealed a pelvic mass on the left side (4.6 cm), at the same site where the first tumor was resected in 2006 (Fig. 3). Once again, extensive studies failed to demonstrate the primary site. Clinically, the second pelvic mass was considered recurrent and excised. The recurrent tumor showed biphasic histology with glandular and spindle sarcomatoid components (Fig. 4A). The cellular spindle components consisted of well-oriented plump spindle cells. These cells consist of alternating darkly stained cells and lightly stained cells arranged in fascicles. The cells were relatively uniform with a small amount of indistinct cytoplasm and oval to short spindle, darkly stained nuclei without prominent nucleoli. Mitoses were occasionally seen, and < 10/10 high power fields were counted. The epithelial tumor component formed solid cords, nests, and glandular structures. The epithelial cells were cuboidal to low columnar with round to oval vesicular nuclei, abundant cytoplasm, and distinct cell boundaries. The glandular lumina contained granular or homogeneous eosinophilic secretions. These two tumor components showed close apposition in a way that the spindle tumor cells surrounded the epithelial tumor component. Scattered thick ropey collagen was seen within the spindle tumor component but no calcifications were observed. Immunohistochemical staining for TLE1 (1:100 dilution, 15-min incubation; clone 1F5, Cell Marque, Rocklin, CA) was performed on the initial (Fig. 2E and F) and recurrent (Fig. 4B) tumors. Both tumors exhibited strong nuclear positivity within epithelial and spindle tumor cells. Pancytokeratin (AE1/AE3), EMA and CK7 were strongly positive in gland-forming tumor cells in both tumors but CK20 was negative. Spindle cells were negative for AE1/AE3, EMA, CK7, and CK20 in both tumors. Bcl-2 and CD99 were positive in spindle cell components of both tumors, but inconsistent in glandular components. S100 and SOX10 are negative for spindle and glandular components in both tumors. 3. Discussion SS is a mesenchymal tumor of unknown origin, which is characterized by the chromosomal translocation t(X;18)(p11;q11) [1]. The 2
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(a)
(b)
(c)
(d)
(e)
(f)
Fig. 2. (A) Original resected tumor mainly shows complex glandular structures with anastomosing and papillary configuration. Focal cellular spindle area (circled) is noted. (H&E, ×50) (B) The gland lumen contains mixed eosinophilic and bluish mucinous secretion. The glandular lining cells have oval to round nuclei with vesicular chromatin and a moderate amount of eosinophilic cytoplasm. Nucleoli are not present or are inconspicuous. (H&E, ×200) (C) The focal cellular area is composed of spindle cells and dense collagenous fibers. Note that the fibrous area is more cellular than is expected in desmoplastic reaction. No significant cytologic atypia or mitotic activity is seen in both glandular and spindle cell components. (H&E, ×200) (D) Intraluminal calcifications. (H&E, ×100) (E, F) TLE1 immunostain in the initial tumor. Nuclear immunopositivity is present not only in glandular but also in spindle stromal element (arrows). (TLE1, ×200).
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diagnosis had been initially made in 2006. Notably, our case had a very unusual clinical course: no recurrence or metastasis occurred until 12 years after resection of the initial tumor, which was misdiagnosed as metastatic adenocarcinoma of unknown primary. Additionally, it is likely that monophasic epithelial SS confers a better prognosis than other subtypes of SS. Notwithstanding the dearth of previous studies on monophasic epithelial SS, Cagle et al. reported that SS with > 50% glandular differentiation, i.e., “highly glandular” SS, has lower 36month recurrence rates and higher survival rates as compared to SS with < 50% of glandular differentiation or monophasic fibrous SS [20]. Other rare but clinically important variants include calcifying SS and poorly differentiated SS. Calcifying SS is characterized by scattered and irregular foci of calcifications, which are present in 30% of SS [21]. Calcifications are an important radiologic clue of SS [22]. Furthermore, calcifying SS has a significantly better prognosis than tumors without calcifications [23]. Poorly differentiated SS can be considered a form of progressed tumor rather than a separate subtype. This variant represents rounded or spindled cells with severe nuclear atypia and high mitotic activity [1]. These tumors tend to behave aggressively and have poorer prognosis [24,25]. The salient features of each SS subtype are summarized in Table 2. 4. Conclusion Monophasic epithelial SS is extremely rare, and has been a controversial entity. Morphologic distinction from metastatic adenocarcinoma can be challenging, and extensive sampling to reveal a cellular spindle cell tumor component is critical. Immunohistochemical staining with TLE1 or molecular studies to detect the t(X;18) translocation is a helpful tool for diagnosis of monophasic epithelial SS. Recognition and proper diagnosis of monophasic epithelial SS is of utmost importance given the different treatment modalities and better prognostic implications as compared to metastatic adenocarcinoma or other types of SS.
Fig. 3. Nonenhanced pelvic computed tomography showed the recurrent mass (4.6 cm) on left side of pelvis (arrow), detected in 2018.
histological and conventional immunohistochemical markers in the appropriate context [2]. For instance, NY-ESO-1 is also an emerging diagnostic and potentially therapeutic marker for SS [18] but this stain is not widely available in daily routine practice yet. Currently, the most reliable diagnostic test for SS is the chromosomal translocation t(X;18) (p11.2;q11.2), which is present in over 90% of SS cases [2,19]. Furthermore, it is important to appreciate and diagnose this rare SS variant in light of the therapeutic and prognostic implications. Complete surgical excision with free margins would have been performed and chemoradiation with a different regimen (ifosfamide rather than 5-FU) would have been administered to our patient if the correct
Funding disclosure We have no financial interest or conflict of interest in association with this work.
(a)
(b)
Fig. 4. (A) Recurrent tumor with biphasic morphology. Tumor shows both glandular and spindle sarcomatoid components, which are apposed to each other. Scattered thick ropey collagen is noted. (H&E, ×200) (B) TLE1 immunostaining of the recurrent tumor demonstrates strong and diffuse nuclear positivity, seen in both epithelial and spindle tumor components. (TLE1, ×200).
4
5
20
47 19
67 48
58 45
Richard M et al. [7]
Weidner et al. [8] K Tajima et al. (1999) [9]
H. Bukawa et al. [10] I Weinreb et al. [11]
Xiohua Jiang et al. [12] Our case
M F
M F
M F
F
M
Right TMJ Left lower leg, posterior tibial nerve Left sphenoidal sinus Left pelvic area
Right distal thigh Left forearm
Left medial thigh
Right flank
Left knee
Right leg Left arm, axilla
Location
NA 5.6
5 8.7
5 3
5
12
7.5c
12 NAc
Sizea Cuboidal or columnar cells with glands, trabeculae, papillary formations Primary: classic biphasic Recurrent: compact aggregates of epithelial cells in a dense, fibrous matrix, cells in files Primary: biphasic with histiocytes; papillary or glandular patterns in the epithelial component Recurrent: uniformly glandular; some undifferentiated areas Primary: 90% glandular nests, frequent intraluminal papillae, squamous differentiation; 10% stromal Recurrent: 90% stromal; 10% atrophic glands 90% cribriforming glands; some papillary, minute spindle components with similar cellularity as desmoplasia Highly vascular, epithelioid tumor cells in a peritheliomatous pattern; a focus of spindle cell area (< 5%) Cuboidal, columnar, polygonal; occasional squamous pearls and keratinization; no spindle cell components Glands with only minute spindle cell components Primary: mucinous secretions, glands, micropapillae, cytologic atypia; < 1% stromal component Recurrent: the same as the primary Atypical proliferating epithelial cells arranged like irregular glands Primary: mostly complex glandular architectures; minor cellular stromal element; foci of intraluminal calcifications; no cytologic atypia or mitotic activity Recurrent: classic biphasic
Histopathology
Abbreviations: TMJ, temporomandibular joint. a Largest dimension in centimeters b Theses two cases were recurrent tumors. The numbers here represent the age when the primary tumor was diagnosed. c Size of the recurrent tumor
25
F
37b
JM Mirra et al. [6]
F F
78 53b
KB Farris et al. [5]
Sex
Age
Reference
Table 1 Previously reported cases of monophasic epithelial synovial sarcoma.
No metastasis for 2 years follow up Recurred at the 3rd month; recurrence free for 11 months thereafter Disease-free for 50 months of follow up Recurred after 12 years
Disease-free for 8 months of follow up Disease free for 4 years of follow up
Disease-free for 30 months of follow up
Recurred as a biphasic tumor after 2 years
Recurred after 13 years
No metastasis for 6 years of follow-up Recurred after 6.5 years
Course
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[1] C.D.M. Fletcher, World Health Organization, International Agency for Research on Cancer, WHO Classification of Tumours of Soft Tissue and Bone, IARC Press, Lyon, 2013. [2] K. Thway, C. Fisher, Synovial sarcoma: defining features and diagnostic evolution, Ann. Diagn. Pathol. 18 (2014) 369–380. [3] L. Guillou, J. Benhattar, F. Bonichon, 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 (2004) 4040–4050. [4] A. Kerouanton, I. Jimenez, C. Cellier, et al., Synovial sarcoma in children and adolescents, J. Pediatr. Hematol. Oncol. 36 (2014) 257–262. [5] K.B. Farris, R.J. Reed, Monophasic, glandular, synovial sarcomas and carcinomas of the soft tissues, Archiv. Pathol. Lab. Med. 106 (1982) 129–132. [6] J.M. Mirra, S. Wang, S. Bhuta, Synovial sarcoma with squamous differentiation of its mesenchymal glandular elements. A case report with light-microscopic, ultramicroscopic, and immunologic correlation, Am. J. Surg. Pathol. 8 (1984) 791–796. [7] R.M. Majeste, E.N. Beckman, Synovial sarcoma with an overwhelming epithelial component, Cancer 61 (1988) 2527–2531. [8] N. Weidner, R. Goldman, J. Johnston, Epithelioid monophasic synovial sarcoma, Ultrastruct. Pathol. 17 (1993) 287–294. [9] K. Tajima, S. Fuyama, H. Yamaguchi, et al., Pure monophasic, epithelial synovial sarcoma without a spindle cell component, Histopathology 34 (1999) 78–81. [10] H. Bukawa, A. Kawabata, A. Murano, et al., Monophasic epithelial synovial sarcoma arising in the temporomandibular joint, Int. J. Oral Maxillofac. Surg. 36 (2007) 762–765. [11] I. Weinreb, B. Perez-Ordonez, A. Guha, et al., Mucinous, gland predominant synovial sarcoma of a large peripheral nerve: a rare case closely mimicking metastatic mucinous carcinoma, J. Clin. Pathol. 61 (2008) 672–676. [12] X. Jiang, Q. Huang, J. Tang, et al., Monophasic epithelial synovial sarcoma accompanied by an inverted papilloma in the sphenoid sinus, Case Rep. Med. 2012 (2012) 379720. [13] Y. Miki, K. Thway, Malignant peripheral nerve sheath tumor with divergent glandular differentiation, Int. J. Surg. Pathol. 25 (2017) 310–313. [14] J.R. Karamchandani, T.O. Nielsen, M. van de Rijn, et al., Sox10 and S100 in the diagnosis of soft-tissue neoplasms, Appl. Immunohistochem. Mol. Morphol. 20 (2012) 445–450. [15] J. Terry, T. Saito, S. Subramanian, et al., TLE1 as a diagnostic immunohistochemical marker for synovial sarcoma emerging from gene expression profiling studies, Am. J. Surg. Pathol. 31 (2007) 240–246. [16] K. Kosemehmetoglu, J.A. Vrana, A.L. Folpe, TLE1 expression is not specific for synovial sarcoma: a whole section study of 163 soft tissue and bone neoplasms, Mod. Pathol. 22 (2009) 872–878. [17] A.L. Valente, J. Tull, S. Zhang, Specificity of TLE1 expression in unclassified highgrade sarcomas for the diagnosis of synovial sarcoma, Appl. Immunohistochem. Mol. Morphol. 21 (2013) 408–413. [18] J.P. Lai, P.F. Robbins, M. Raffeld, et al., NY-ESO-1 expression in synovial sarcoma and other mesenchymal tumors: significance for NY-ESO-1-based targeted therapy and differential diagnosis, Mod. Pathol. 25 (2012) 854–858. [19] A.A. Sandberg, J.A. Bridge, Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. Synovial sarcoma, Cancer Genet. Cytogenet. 133 (2002) 1–23. [20] L.A. Cagle, J.M. Mirra, F.K. Storm, et al., Histologic features relating to prognosis in synovial sarcoma, Cancer 59 (1987) 1810–1814. [21] N.L. Cadman, E.H. Soule, P.J. Kelly, Synovial sarcoma; an analysis of 34 tumors, Cancer 18 (1965) 613–627. [22] M.D. Murphey, M.S. Gibson, B.T. Jennings, et al., From the archives of the AFIP: imaging of synovial sarcoma with radiologic-pathologic correlation, Radiographics: A Review Publication of the Radiological Society of North America, vol. 26, Inc, 2006, pp. 1543–1565. [23] J. Varela-Duran, F.M. Enzinger, Calcifying synovial sarcoma, Cancer 50 (1982) 345–352. [24] M. van de Rijn, F.G. Barr, Q.B. Xiong, et al., Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features, Am. J. Surg. Pathol. 23 (1999) 106–112. [25] M.V. de Silva, A.D. McMahon, L. Paterson, et al., Identification of poorly differentiated synovial sarcoma: a comparison of clinicopathological and cytogenetic features with those of typical synovial sarcoma, Histopathology 43 (2003) 220–230.
Poor
Either monophasic or biphasic; round or spindle cells with nuclear atypia, mitoses, or necrosis Round cell neoplasms (e.g., EFT, neuroblastoma, rhabdomyosarcoma, lymphoma, etc.)
References
Abbreviations: MPNST, malignant peripheral nerve sheath tumor; SS, synovial sarcoma.
Intermediate Prognosis
Spindle cell neoplasms (e.g., fibrosarcoma, leiomyosarcoma, MPNST, etc.) Intermediate
Histology
Differential diagnosis
Biphasic neoplasms (e.g., MPNST, mesothelioma, carcinosarcoma, etc.)
Good
Either monophasic or biphasic; irregular calcifications Extraskeletal osteosarcoma, myositis ossificans, ossifying fibroma, etc. Good Epithelial (most commonly glandular) cell dominant Metastatic adenocarcinoma, adnexal carcinoma, carcinosarcoma, etc.
20% 30%
The authors thank Dr. Helen Chifotides for her editorial support.
72% in adults 55% in children Spindle cell dominant
28% in adults 45% in children Biphasic
Very rare
Acknowledgment
Incidence
Monophasic fibrous SS
Table 2 Salient features of different types of synovial sarcoma.
Biphasic SS
Monophasic epithelial SS
Calcifying SS
Poorly differentiated SS
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